Synergistic Effect and Molecular Mechanisms of Traditional Chinese Medicine on Regulating Tumor Microenvironment and Cancer Cells

Xu, Jingnan; Song, Zhuo; Guo, Qiujun; Li, Jie

doi:https://doi.org/10.1155/2016/1490738

BioMed Research International

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Interplay between Tumor Microenvironment and Cancer Cells

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Review Article | Open Access

Volume 2016 | Article ID 1490738 | https://doi.org/10.1155/2016/1490738

Synergistic Effect and Molecular Mechanisms of Traditional Chinese Medicine on Regulating Tumor Microenvironment and Cancer Cells

Jingnan Xu,^1,2Zhuo Song,^1,3Qiujun Guo,^1,2and Jie Li¹

Academic Editor: Kallesh D. Jayappa

Received25 Dec 2015

Accepted26 Jan 2016

Published02 Mar 2016

Abstract

The interaction of tumor cells with the microenvironment is like a relationship between the “seeds” and “soil,” which is a hotspot in recent cancer research. Targeting at tumor microenvironment as well as tumor cells has become a new strategy for cancer treatment. Conventional cancer treatments mostly focused on single targets or single mechanism (the seeds or part of the soil); few researches intervened in the whole tumor microenvironment and achieved ideal therapeutic effect as expected. Traditional Chinese medicine displays a broad range of biological effects, and increasing evidence has shown that it may relate with synergistic effect on regulating tumor microenvironment and cancer cells. Based on literature review and our previous studies, we summarize the synergistic effect and the molecular mechanisms of traditional Chinese medicine on regulating tumor microenvironment and cancer cells.

1. Introduction

Tumor microenvironment (TME) plays a pivotal role in the process of cancer development and metastasis. Tumor and its microenvironment are a complex compound including the “seed” and “soil,” which was first proposed by Stephen Paget; a hypothesis suggested that the sites where metastases occur were defined not only by the tumor cell (seed) but also by the microenvironment of the secondary metastatic site (soil) [1]. Until recently, the staging and treatment approaches for cancer appeared to be orientated predominantly to both “soil” and “seed.” We are currently witnessing an increasing amount of evidence, spanning from clinical to laboratory research, which highlights that cancer growth and metastasis are the result of the dynamic balance between the cancer itself and the impaired function of the TME [2]. Target organs can release various cytokines recruiting tumor cells, promoting cell proliferation, and inducing angiogenesis and eventually form metastases. At the same time, tumor cells can also release various cytokines by paracrine manner, remodeling TME for their own survival. Therefore, the interaction between tumor cells and TME of target organ facilitates a complex metastasis process. Increasing evidence indicates that TME is a key target of tumor therapy research, because of its special physical and chemical properties and the internal relations between inflammation and immune system [3]. The final purpose of target therapy on TME is effectively resisting the interaction between tumor cells and their microenvironment. However, conventional cancer treatments mostly focused on tumor cell and single targets or single mechanism, on the basis of the fact that few researches intervene in the whole TME [4]. In recent years, researches of antitumor drugs focused on remodeling TME emerge endlessly, mainly targeting antiangiogenesis and immunotherapy to overcome the immune tolerance, treatment reversing drug resistance, and so forth. Unexpectedly, antiangiogenesis drugs did not achieve the ideal treatment effect; on the contrary they produce greater toxicity and promote the development of tumor as a result of hypoxia and reduction of transmission chemotherapy drugs to tumor tissue, promoting tumor drug resistance; tumor cells can get nutrition energy supplement through autophagy from TME and eventually make the antiangiogenesis therapy only show decreasing repair ability of normal tissue [5]. Tumor immunotherapy has become an important means to prevent tumor recurrence and metastasis. Most current tumor immunotherapy has shown good effect of tumor destruction in vitro but did not reach expected effect in vivo, for it cannot overcome the tumor antigen-presenting and immune effectors function inefficiency. Conventional tumor chemotherapy resistance research mainly focused on the genetic changes of endogenous factors. A large number of studies have shown that the TME played an important role in mediating acquired drug resistance [6].

In cancer treatment, traditional Chinese medicine (TCM) emphasizes the overall efficacy, inhibiting tumor cell as well as TME to suppress tumor development and recurrence. So far, many Chinese herbs have been shown to have a good effect in clinical studies, which display a broad range of clinical effects including alleviation of cancer-associated symptoms, prolonging survival rates, decreasing treatment-related toxicity, and preventing recurrence and metastasis [7–15], as shown in Table 1. Furthermore, several Chinese herbs have also been proven to inhibit tumors in fundamental experiments. Although the mechanism of TCM is still unclear, increasing evidence has shown that it may relate with synergistic effect on regulating TME and cancer cells. In this review, we will summarize the synergistic effect and the molecular mechanisms of TCM on regulating TME and cancer cells according to recent researches.

2. TCM Regulates Tumor Microenvironment

The TME encompasses a complex meshwork of nonmalignant cells, structural components, molecules, and chemicals that surround cancer cells. The nonmalignant cells, including endothelial cells, pericytes, fibroblasts, and immune cells, together with the surrounding extracellular matrix (ECM), comprise the supportive stroma of the tumor and modulate the TME [16]. The production of both tumor-promoting and tumor-suppressing signals from these various cell types influences the tumor microenvironment. Recently, targeting TME has opened new avenues in clinical oncology [17]. However, treatment itself activates the microenvironment by damaging a large population of cells, which can drastically exacerbate disease conditions in a cell in a nonautonomous manner, and such off-target effects should be well taken into account when establishing future therapeutic rationale [18]. TCM is a potential treatment strategy.

2.1. TCM Inhibits the Degradation of Extracellular Matrix

The tumor microenvironment consists of an insoluble ECM, a stroma composed of fibroblasts, adipocytes, and endothelial and resident immune cells, and a multitude of growth factors and cytokines [19]. Abnormal changes in the amount and organization of molecules lead to altered biochemical and physical properties of tumor-associated ECM that contributes to tumor progression and resistance to therapy [20, 21]. Matrix metalloproteinases (MMPs) are enzymes that degrade structural components of the ECM, produced by cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TAN), mast cells (MCs), blood endothelial cells (BECs), lymphatic endothelial cells (LECs), and bone marrow-derived mesenchymal stem cells (MSCs). These enzymes regulate a multitude of physiological processes such as morphogenesis, tissue remodeling, and signaling events [22]. Its activity has been implicated in almost every stage of the metastatic cascade from the primary site to the progression of tumor extravasation, growth, and development. The expression and activity of MMPs against matrix macromolecules have been associated with the development of malignant phenotypes and the promotion of cell invasiveness and metastasis [23]. Several studies show that MMP-2 and MMP-9 are highly expressed in tumors and are associated with poor clinical outcome. Some traditional Chinese medicine monomers and compounds have been reported to have inhibitory effects on the migration and invasion of cancer cells via reducing the expression of MMPs [24, 25].

Deng et al. illustrated YQFS (a standard formulation of Si-Jun-Zi-Tang with the addition of Myristica fragrans and five-leaf Akebia fruit) extract had an antitumor effect, which could be attributed to ERK1/2-dependent inhibition of MMP-2/9 expression, modulating the ERK/MAPK pathway and its downstream factors by selectively targeting ERK phosphorylation [24]. Momordica cochinchinensis (a Chinese herbal called Mu BieZi) has been used for a variety of purposes, showing an anticancer action. Zheng et al. found that extracts of Momordica cochinchinensis seeds (ESMCs) revealed strong growth inhibitory effects on ZR-75-30 cells and effectively inhibit ZR-75-30 cell invasion in a dose-dependent manner. ESMC treatment could not only reduce the protein expression but also repress the enzymatic activity of MMP-2 and MMP-9, which suggests that ESMC’s anti-invasive action was mediated by diminishing the ability of breast cancer cells to degrade the components of ECM by modulating MMP-2 and MMP-9 expression and activity [26].

2.2. TCM Improves the Hypoxia Microenvironment

Abnormal and dysfunctional blood vessels in tumor tissues are incapable of restoring oxygenation, therefore perpetuating hypoxia, which, in turn, will fuel tumor progression, metastasis, and resistance to antitumor therapies [27]. Increasing evidences indicate that the vasculature is insufficient to supply adequate oxygen when solid tumor diameter is >2 mm, resulting in local hypoxic and anoxic conditions inside the tumor. The level of hypoxia within a tumor increases during tumor progression and is a good indicator of disease outcome because hypoxia selects the most invasive cancer cells and promotes resistance to therapies [28–30]. Factors in the response of tumor cells to this distinct microenvironment are the activities of the hypoxia inducible factor-1α (HIF-1α), which is regulated in an oxygen-dependent manner [31]. HIF-1α signaling pathway is frequently observed in solid tumors and is strongly associated with numerous pathophysiological processes, including the induction of epithelial-mesenchymal transition (EMT), a process in which epithelial cells lose cell-cell adhesion and cell polarity and acquire properties of mesenchymal cells, which results in cancer progression, metastasis, and multidrug resistance in cancer [32–35].

Pien Tze Huang (PZH) has been used in China and Southeast Asia for centuries as a remedy for various types of human cancer. It was found that treatment with PZH was observed to significantly decrease the cell migration and invasion rates and inhibit the hypoxia-mediated EMT and HIF-1 signaling, suggesting that PZH concentration dependently inhibits the hypoxia-induced metastasis of colon cancer cells [35]. Another study showed that Oroxylin A remarkably inhibited HIF-1α expression and its stability and also suppressed the downstream targets (e.g., PDK1, LDHA, and HK II) and their mRNA levels under hypoxia. Furthermore, Oroxylin A could decrease the accumulation of ROS, which was benefit for inhibition on glycolytic activity by decreasing ROS-mediated HIF-1 expression. PI3K is an important molecular signal transduction in tumor cells and an upstream signal pathway molecular of HIF-1α [36]. Wogonin, extracted from the TCM herb Scutellaria baicalensis, was recently found to be a good candidate for the development of new multidrug resistance (MDR) reversal agent and its reversal mechanism was due to the suppression of HIF-1 expression via inhibiting PI3K/Akt signaling pathway [37, 38].

2.3. TCM Reverses the Immunosuppressive Microenvironment

Suppressive phenotypes of immune cells are regulated and reversed by TCM treatment. Concretely, inflammatory T cells and natural killer T cells (NKT) increasingly proliferate in contrast of the reducing quantity of regulatory T cells and myeloid-derived suppressor cells (MDSCs) after treatment by TCM. Furthermore, suppressive macrophages and dendritic cells (DCs) change their functions to antitumor effects, such as M2 to M1 phenotype reversing and DCs maturation by increasing inflammatory factors expression and immune suppressive cytokines decreasing [16].

The major function of DCs is to process and present antigen for the activation of CD4⁺ and CD8⁺ T cells. Endocytosis of antigen by immature DCs drives DCs maturation and the subsequent presentation of antigen to T cells [39]. However, the tumor microenvironment systemically perturbs this process by increasing the accumulation of immature DCs and decreasing DCs maturation. As a result, DCs fail to activate T cells. Defective DCs function has been found in many patients with a variety of cancers, such as pancreatic carcinoma, cervical squamous intraepithelial lesions, hepatocellular carcinoma, and non-small cell lung cancer [39–43]. Multiple conditions and factors within the TME cause DCs abnormalities, including hypoxia, lactic acid build-up, and adenosine accumulation. Astragalus mongholicus (AMs) is a common herbal of TCM and has been proved to be effective in treating cancers according to abundant clinical case reports. Tian et al. investigated the effect and mechanism of AMs on human stomach cancer. It turned out that AMs is effective in treating stomach cancer and it might precipitate DCs maturation by regulating TLR4 mediated NF-κB signal transduction against tumor [44].

MDSCs are a major host component contributing to the immune suppressive environment, inhibiting both adaptive and innate antitumor immunity through different ways, such as inhibiting T cell activation and function and suppressing natural killer cell (NK) cytotoxicity [16]. MDSCs represent a heterogeneous population, including immature macrophages, DCs, and granulocytes, generated by and released from the bone marrow in response to a wide array of pathological stimulations like malignant tumor and inflammation, leading to the expansion of MDSCs and contributing to the negative regulation of tumor immune response [45]. The MDSCs can inhibit T cell-mediated tumor acquired immune responses with overexpression of Arg1, iNOS, and Ros, suppress NK cell cytotoxicity by inhibiting NKG2D and IFN-c, and facilitate angiogenesis by releasing vascular endothelial growth factor (VEGF), MMPs, and TGF-β [46]. Wang et al. investigated the effect of ginseng-derived compound K (C-K) on apoptosis, immunosuppressive activity, and proinflammatory cytokine production of MDSCs. It turned out that C-K treatment can significantly increase the percentages of early and late apoptotic MDSCs in vitro, decrease the expressions of immunosuppression-related genes Cox-2 and Arg-1, and suppress the function of IL-1β, IL-6, and IL-17, which implied that C-K can restrain the immunosuppressive effect of MDSCs to inhibit tumor cell proliferation in mice [47].

Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells with a potential to promote cancer cell proliferation and invasion and regulate tumor neovascularization and lymphangiogenesis, as well as cytotoxic T cell function [47]. Under pathological conditions, macrophages acquire distinct phenotypic characteristics through different activation mechanisms [48]. The classical activated macrophage (M1-like) exhibits proinflammatory properties by expressing and secreting proinflammatory molecules (e.g., TNF-α, IL-6, IL-12, IL-1, Type I, IFN-γ, CXCL1–3, CXCL-5, and CXCL8–10), while macrophage could be alternatively activated to M2-like phenotype, which expresses anti-inflammatory factors (e.g., VEGFC/D, VEGFR3, MMPs, IL-10, and IL-13) [49–52]. Several researchers have reported TCM could switch the phenotype of TAMs from M2 to M1, inhibiting tumor progression. Baicalin is a natural flavonoid from medicinal herbs including Scutellaria baicalensis Georgi. Several studies have revealed the antitumor action of Baicalin by increased expressions of IFN-γ and IL-12 to activate immune response. Recent study results showed that Baicalin can initiate TAM reprogramming to M1-like macrophage, induce repolarization of TAM and M2-like macrophage through autophagy and transcriptional activation of RelB/p52 pathway, and promote proinflammatory cytokines production [53, 54].

2.4. TCM Inhibits Angiogenesis

The growth and metastasis of the tumor depend on an effective microcirculation. The formation of a microcirculation can occur via the traditionally recognized mechanisms of angiogenesis and vasculogenic mimicry (VM). It is well established that angiogenesis is necessary for the tumor progression and metastasis [55]. Angiogenesis occurs by complex sequential steps, such as basement membrane degradation by proteases, endothelial cell proliferation and migration/invasion, formation of capillary tubes, and survival of newly formed blood vessels, which is tightly regulated by an intricate balance between stimulators and inhibitors such as VEGF, fibroblast growth factor, and MMPs [56]. Among them, VEGF is the most important angiogenic factor closely associated with neovascularization in human tumors [57]. VM is a novel tumor blood supply in some highly aggressive malignant tumors, provides a special passage without endothelial cells, and is conspicuously different from vasculogenesis [58]. VM has unique ability of highly aggressive tumor cells to express endothelial cell-associated genes and form ECM-rich, patterned tubular networks when cultured on a three-dimensional (3D) matrix and is associated with a poor prognosis for the patients with some aggressive malignant tumors [59, 60].

Ginsenoside Rg3, a saponin extracted from ginseng, has been demonstrated to have anticancer activity in vitro and in vivo with relatively low toxicity, especially on vessels or angiogenesis in tumors [61]. A study aimed to investigate the antiangiogenic effects of Rg3 in patients with acute leukemia. The results showed that Rg3 exhibited antileukemia effect in part due to its antiangiogenic activity via inhibiting PI3K/Akt and ERK1/2 pathways, which act to regulate the expression of HIF-1α and VEGF [62]. The rhizome of Atractylodes lancea is extensively used in Chinese medicine as crude extracts/decoctions or a component in various herbal formulations. Numerous studies have reported the anticancer activities of Atractylodes lancea [63]. CLT, also named Atractylenolide III, is the major bioactive component of Atractylodes lancea. Wang et al. demonstrated CLT inhibited the development of angiogenesis both in vitro and in vivo. Similar to its effects on cancer cells, the inhibitory effect of CLT on ECs was due to its ability to inhibit MMPs expression and VEGF secretion by downregulating Runx2 activation of ECs, which may be associated with interference with BMP signaling in endothelial cells [64]. Abundant studies have demonstrated that PZH could suppress multiple colorectal cancers and associated signaling pathways, leading to the promotion of cancer cell apoptosis and the inhibition of cell proliferation and tumor angiogenesis [65–70].

Most antiangiogenic therapies currently being evaluated target the VEGF pathway. However, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Recent studies have identified fibroblast growth factor 1 (FGF1) as a direct activator of PI3K-Akt, which is a non-VEGF angiogenic pathway to initiate endothelial cell migration, invasion, and differentiation. Ferulic acid (FA), an effective component of many Chinese medicinal herbs, like Cimicifuga heracleifolia, Angelica sinensis, and Lignsticum chuangxiong, exhibits anti-inflammatory and anticancer activities. A study indicated that FA exerted antiangiogenesis activities at a nontoxic dosage via specifically targeting fibroblast growth factor receptor 1 (FGFR1) and its PI3K/Akt signaling pathway in melanoma [71].

2.5. TCM Inhibits Lymphangiogenesis

There is accumulating evidence that tumor-associated lymphangiogenesis is an important feature of tumor progression and may facilitate cancer cell dissemination to the lymph nodes [72, 73]. Accordingly, numerous clinical studies have demonstrated a significant correlation between lymphatic vessel density and lymph node metastasis. Clinical evidence suggests that the VEGF family members VEGF-C and VEGF-D are major lymphangiogenic regulators by binding to VEGFR-2 and VEGFR-3, which are expressed on LECs. Higher VEGF-C expression is associated with higher peritumoral lymphatic vessel density, increased lymphatic invasion, and increased lymph node metastasis [74]. Kimura and Sumiyoshi discovered Wogonin isolated from Scutellaria baicalensis roots could inhibit VEGF-C-induced lymphangiogenesis through a reduction in VEGF-C-induced VEGFR-3 phosphorylation [75]. Norcantharidin (NCTD) is a demethylated and low-cytotoxic derivative of cantharidin with antitumor properties, an active ingredient of the traditional Chinese medicine Mylabris. It has been reported that NCTD is used selectively in clinic to treat hepatic, gastric, colorectal, and ovarian carcinomas and leucopenia in China because of its effective anticancer activity, fewer side effects, and leukocytosis [76–81]. A study showed that NCTD inhibited tumor growth and lymphangiogenesis of HCACs through “multipoints priming” mechanisms, that is, directly or indirectly downregulating VEGF-A, -C, -D/VEGFR-2, -3 signaling pathways, which strongly suggested that NCTD could serve as a potential antilymphangiogenic agent for tumor lymphangiogenesis [82]. Nagy et al. demonstrated that, in addition to angiogenesis, VEGF-A also induced proliferation of lymphatic endothelium, resulting in the formation of greatly enlarged and poorly functioning lymphatic channels, and abnormal lymphangiogenesis. These findings raise the possibility that abnormal lymphangiogenesis may also be expected in other circumstances such as malignant tumors characterized by VEGF-A overexpression [81].

3. TCM Inhibits the Development of the “Seed”

Just as the role of a seed in growth, cancer cells play a pivotal role in the process of tumor occurrences, developments, and metastasis, which are always the focus and hot areas of tumor researches. It was reported that this “Seed” can proliferate immortally and activate invasions and metastasis [83]. In addition, tumor cells were also deemed to be the initiators of tumor microenvironment formation, which reversely promote the growth of tumor cells [84]. Nowadays, surgery, radiotherapy, and chemotherapy are three major treating strategies of tumors for minishing burden and inhibiting growth, which have been widely used and achieved effects in clinic [85]. However, these targeted treatments were reported to have some degree of adverse effect with them. TCM, as an important complementary strategy, has also been shown to possess therapeutic effects on cancer cells. The followings may be the principle and potential molecular mechanisms for TCM in cancer treatment.

3.1. TCM Inhibits the Growth of Cancer Cells

Proliferation and apoptosis of cells are two critical factors that determine organism development and tissue homeostasis [86, 87]. Precisely, it is the unrestricted proliferation and suppressed apoptosis that make cancer cells grow frantically and malignantly. Accumulating studies have revealed that dysfunction in cell cycle regulation often resulted in abnormal proliferation of cancer cells [88]. The regulation of the cell cycle is influenced by many molecules such as cyclins, CDKs, and CDKIs and through Akt and MAPK signaling pathways [89]. In addition, p53, a major mediator of cell cycle arrest, was reported to mutate or be inactivated in several tumors. If that happened, the apoptotic response is not activated and cell proliferation is allowed [90]. Studies have shown that p53 can upregulate the level of p21 and Gadd45 to mediated cell cycle arrest [91–95]. Others also implicated that p53 upregulated proapoptotic Bax and downregulated prosurvival Bcl-2 to mediate apoptosis [96, 97]. Several mechanisms also demonstrated that overexpression of Bcl-2 increases the activity of AKT and IKK as well as NF-κB transcriptional activity in cancer [98]. TCM has been reported to inhibit the growth of cancer cells in abundant clinical trials. Although the mechanisms are not very clear, increasing data has shown that they maybe relate with above-mentioned regulating biomarkers to inhibit proliferation and induce apoptosis of cancer cells. The confirmed mechanisms of herb compounds and monomers acting common cancers are listed in Table 2 [86, 88, 91, 92, 95, 97, 99–103].

3.2. TCM Prevents Invasion and Metastasis of Tumor Cells

Despite the fact that all available treatments had been implemented, local invasion and metastasis predict a poor prognosis and contribute to more than 90% of tumor mortality [104, 105]. Therefore, it is needed to gain further insight into the molecular mechanisms on invasion and metastasis of tumor cells and to search for more effective therapies. Extracellular matrix (ECM) is related to the tumor cell invasion and metastasis, and, as we know, the abnormal and absent expression of ECM has been found in many malignant cells [106]. In tumor microenvironment, tumor cells can degrade and remodel the ECM by excessively secreting matrix MMPs such as MMP-2 and MMP-9 [107]. In the meantime tumor cells also conducted epithelial-to-mesenchymal transition (EMT) process, downregulating E-cadherin expression and overexpressing N-cadherin and vimentin [108, 109], which weakens intercellular adhesive attractions. In addition, increased levels of phosphorylated p38α could downregulate fibulin-3 expression through hypermethylation of regulatory sequences of the gene and then facilitated the invasion and metastasis of tumor cells [110].

TCM can prevent invasion and metastasis of tumor cells via inhibiting ECM degradation and EMT process. Fei-Liu-Ping (FLP) ointment is an oral prescription medication that is used to treat lung cancer patients in China, which has been shown to possess anticancer properties [64]. Li et al. revealed that FLP could inhibit A549 cell invasion and metastasis by increasing E-cadherin expression and decreasing the expression of N-cadherin and MMP9. They also found that FLP performed synergistic effect when combined with cyclophosphamide (CTX) [111]. Baicalein, another antineoplastic compound of Chinese herbs, also inhibited the expression of MMP-9 and MMP-2 via reducing expression of protein kinase Cα (PKCα) and p38 mitogen-activated protein kinase (p38 MAPK) levels in poorly differentiated hepatoma cells [112]. The anti-invasive and antimigratory effects of TCM were also found in curcumin researches. Curcumin can prevent the invasion of hepatocellular carcinoma through inhibiting the production of MMP-9. In addition, it was found that curcumin significantly inhibited adhesion and haptotactic migration to fibronectin and laminin without affecting the expression of integrin on the cell surface. Furthermore, it could also affect the formation of actin stress fibers [113].

3.3. TCM Reverses the Immunosuppressive Phenotype of Tumor Cells

As the immune-editing theory says, immune system plays a critical role in maintaining equilibrium between immune recognition and tumor development, with a dual capacity to both promoting and suppressing tumor growth [114]. During cancer immune editing, the immune system is able to recognize and destroy the most immunologically vulnerable cancer cells. Nonetheless, due to genetic instability, constant tumor cell division generates with reduced immunogenicity that can evade immune elimination [115]. Furthermore, tumor cells can also vary several immune phenotypes to impair the capacity of the immune system to eradicate them by immune suppressive effects [116]. In the recent years, studies have shown that, while being treated by TCM, the expression of programmed cell death protein-1 (PD-1) was decreased. Classic major histocompatibility complex (MHC) and Fas molecules were expressed more on tumor cytomembranes, which leaded tumor cells to be recognized easier and killed by the immune system. In conclusion, TCM can exert a biphasic regulation on tumor cells phenotype to enhance antitumor immune responses.

3.3.1. TCM Promotes Classic MHC Molecules Expression

MHC is the important immunological recognition molecule in the process of tumor immune response. Classic MHC molecule can be divided into two subgroups: MHC I and MHC II; both of them reinforce the interactions of cytotoxic T cell (CTL) or NK cells with tumor cells by presenting tumor antigens to them [117]. However, immune and malignant cells in the tumor microenvironment do not express typical MHC molecules but overexpress sHLA and sNKAL, which may lead to killing CTL and NK cell mediated by apoptosis [118]. Increasing data has shown that TCM can efficiently reverse this harmful phenomenon. Li et al. explored the effect of Invigorating Spleen and Detoxification Decoction (ISD) (Radix Codonopsis, Poria, Rhizoma Atractylodis Macrocephalae, Radix Glycyrrhizae, Radix Bupleuri, Rhizoma Curcumae, and herba Scutellaria barbata) on MHC molecules in the rat liver cancer tissue and found that ISD could enhance the expression of MHC I and MHC II both in tumor and in liver tissue, besides prolonging the survival time and decreasing the incidence of cachexia [119].

3.3.2. TCM Reverses the FasL/Fas Expression of Tumor Cells

FasL and its receptor Fas are membrane-bound glycoproteins; the activation of them plays an important role in cell apoptosis. Physiologically, cytotoxic T lymphocytes () express FasL combined with the Fas expressing cells (), resulting in the activation of the Fas receptor, and then mediate target cells apoptosis [120]. However, loss of Fas and gain of aberrant FasL expression are common features of malignant transformation, such as FasL and sFasL, which in turn combined with Fas express lymphocytes and eliminated their activated immune reactions [121]. Our previous study showed that TCM formula Yang Wei Kang Liu (YWKL) (Radix Astragali, Radix Ginseng, Hedyotis diffusa, Yunnan Manyleaf Paris Rhizome, Radix Notoginseng, Radix Paeoniae Rubra, and Hematoxylon) could increase Fas expression, downregulate FasL-mRNA expression in MGC-803 stomach cancer cell model in vitro, and induce the apoptosis of MGC-803 cells. Together with the previous research, it indicated that potential mechanisms of YWKL inducing gastric cancer cells apoptosis might be through regulating Fas/FasL pathway so as to enhance cancer cells’ sensitivity to immune response cells like CTL [122].

3.3.3. TCM Decreases the Expression of PD-L1

PD-1, which is expressed on activated T and B cells, natural killer cells, and myeloid cells, is an another immune checkpoint [123]. Two ligands for PD-1 have been identified: PD-L1 and PD-L2. Researches indicated that PD-L1 was overexpressed by various tumor cells, including breast cancer, thyroid carcinomas, lung, colon, ovarian, melanoma, bladder, liver, salivary, stomach, and gliomas [124]. PD-L1 can engage the PD-1 receptor and induce T cell exhaustion and eventually inhibit T cell activation and proliferation. Thus, the interaction between PD-1 and its ligands, especially PD-L1, may contribute to the immune evasion of cancer cells [124]. Recently, Wang et al. found that Astragalus polysaccharide (APS), extracted from TCM herb Astragalus, could significantly inhibit the growth of B16-F10 melanoma cells in a transplant model and decreased the expression of both PD-L1 protein and PD-L1 mRNA in tumor. This indicated that mechanism may be related to regulating PD-1/PD-L1 pathway to enhance the antitumor immune activity of T lymphocytes [125].

3.4. TCM Reverses the Drug Resistance of Tumor Cells

Over the past few decades, the efficiency of endless chemotherapies did not reach what we have expected. Some experts attributed this phenomenon to the multidrug resistance (MDR) [126]. It was reported that major mechanical of MDR in tumor cells was the overexpression of a membrane-bound protein, P-glycoprotein (P-gp), and other members of the adenosine triphosphate (ATP) binding cassette (ABC) transporter superfamily [127], which translocate a substrate from the intracellular compartment to the extracellular compartment, leading to a reduced intracellular concentration of the substrate and resistance to antineoplastic drugs [128]. However, several other mechanisms are also involved in the development of MDR in tumor cells, including alterations in drug targets, the activation of detoxifying systems, the interruption of signaling pathways, and alterations in regulators involved in cell cycle control [128].

Recently, accumulated basic researches have proven that TCM could reverse multidrug resistance of tumor cells through several pathways. Yiqi Jianpi Huaji Decoction (YJHD), a traditional Chinese medicinal formula composed of twelve ingredients, has recently been reported to have a good clinical therapeutic effect. Li et al. found that low dose YJHD could reverse MDR and increase sensitivity of cancer cells to chemotherapeutic agents in vitro by downregulating P-gp, MRP, TUBB3, and STMN1 expression [129]. MDR can also be reversed by siRNAs targeting genes involved in MDR. Eid et al. also reported that Fallopia japonica (FJ) could modulate the function of ABC drug transporters to overcome multidrug resistance in cancer cells [130].

5-Fluorouracil (5-FU), a common chemotherapeutic agent used for tumor treatment, by itself has inadequate response rates, highlighting the need for improving the effects for these patients [131–134]. Baicalein, a flavonoid derived from the root of Scutellaria baicalensis, was reported to increase the sensitivity of AGS cells to 5-FU treatment under hypoxia. In addition, the hypoxia-enhanced glycolytic flux and expression of several critical glycolysis-associated enzymes (HK2, LDH-A, and PDK1) in the AGS cells were suppressed by baicalein. These findings suggested that inhibition of glycolysis via regulation of the PTEN/Akt/HIF-1α signaling pathway might be one of the mechanisms whereby baicalein reverses 5-FU resistance in cancer cells under hypoxia [131].

Sorafenib, a standard first-line therapeutic treatment for patients with advanced hepatocellular carcinoma (HCC), is also demonstrated to be hampered by the development of drug resistance in recent years [134, 135]. The activation of Akt by sorafenib was thought to be responsible for this resistance [136]. It was found that Bufalin, which is the major active ingredient of the traditional Chinese medicine Chan Su, could inhibit Akt activation and reverse drug resistance to sorafenib. Further studies reported that bufalin reversed acquired resistance to sorafenib by downregulating phosphorylated Akt in an ER-stress-dependent manner via the inositol-requiring enzyme 1 (IRE1) pathway [137].

3.5. TCM Attenuates Oncogenicity of CSCs

Cancer stem cells (CSCs) existing in the tumor play a crucial role in carcinogenesis though in a very few quantity [138]. Julius Cohnheim once inferred that tumors might arise from stem cells left over from embryonic development [139]. Recently, researches have further demonstrated that CSCs had the ability of self-renewing, invasion, metastasis, immunosuppressive, and multidrug resistance. Hence, CSCs are proposed to be the main cause of cancer relapse after resisting several therapies [140]. Evidences showed that TCM attenuated oncogenicity of CSCs. When treated with bufalin, the sphere of CSCs could not get attached to the flask and failed to differentiate, which was indicated by the stable expression of stem cell marker CD133 and OCT-4 in the condition permissive to differentiation. Treatment of bufalin also suppressed the single cells isolated from the sphere to form sphere again in the nonadhesive culture system, and a decreased expression of proliferation marker Ki67 was also detected in these cells [141]. Besides, CSCs tumor spheres lowly expressed Fas and highly expressed membrane complement regulatory proteins and Foxp3, which were associated with a high frequency of metastasis [142]. Some medicinal herbs had been proved to reverse CSCs immune suppression and suppress CSCs metastasis via dual-blocking epithelial-mesenchymal transition (EMT) and CSCs properties [143]. Pien Tze Huang (PZH), a well-known and ancient TCM formula, was reported as an operative medicine that significantly and does-dependently inhibited the viability and promoted the apoptosis and differentiation of the colorectal CSCs via suppressing the Notch1 pathway. Studies also revealed that PZH markedly inhibited the mRNA levels of ABCB1 and ABCG2, which are members of the ATP-binding cassette (ABC) transporter superfamily, thereby contributing to the side population phenotype and multidrug resistance [144].

4. Summary

The mutual and interdependent interaction between tumor and its microenvironment is a crucial topic in cancer research. Previously, we have made headways in understanding and preventing tumors, but most of them are focused only on cancer cells. Recently, accumulated data indicates that TME played a crucial role in protecting cancer cells [145]. Studies declare that tumor microenvironment consists of cells, soluble factors, signaling molecules, extracellular matrix, and mechanical cues that can promote neoplastic transformation, support tumor growth and invasion, protect the tumor from host immunity, foster therapeutic resistance, and provide niches for dormant metastases to thrive [145]. Thus, multiple abnormal segments have existed in malignant diseases. The synergistic interplay between tumor cells and microenvironment plays a key role in the progress of cancer, for which can offset the actions of soloes target for drugs [146]. So it has become a new trend for researchers to block the interplay between tumor and microenvironment via comprehensive treatments and combined application of drugs.

A better understanding of interplay between tumor cells and microenvironment may be a crucial key to improve therapeutic efficacy. For example, it was well known that radiotherapy directly caused cancer cells death through the induction of DNA damage. In the meantime irradiated tumors stimulated the immune system and caused immunogenic cell death by releasing tumor antigens and damage-associated molecular patterns, which promotes the uptake of dying cells and triggers a cytotoxic T-lymphocyte response [147, 148]. Zegers et al. finally demonstrated that radiotherapy combined with the immune cytokine L19-IL2 could provide long-lasting antitumor effects [148]. Therefore, compared with antitumor immune response that radiotherapy provides alone, the addition of active immunotherapy may increase the therapeutic potential. In addition, it was reported that dying tumor cells through the apoptosis generated potent growth-stimulating signals to stimulate the repopulation of tumors undergoing radiotherapy. And activated caspase 3, a key executioner in apoptosis, was also involved in the growth stimulation [149].

When targeted, cancer cells alter the surrounding tumor microenvironment to protect themselves. Although studies showed that TCM inhibit the cancer cell growth and tumor microenvironment through various mechanisms (Figure 1), the interplay between the tumor cells and microenvironment is not clear. By understanding the mechanisms by which TCM inhibits tumor cells and microenvironment, novel cancer therapeutics can be evolved.

Figure 1

The confirmed mechanism of TCM on tumor cells and microenvironment. TCM can inhibit “seeds” and regulate “soil” to suppress tumor development and recurrence via diverse ways. The mechanism of TCM inhibiting tumor “seeds” includes inhibiting growth, invasion, metastasis of cancer cells, and reversing immunosuppressive phenotypes and drug resistance. Meanwhile, TCM regulates “soil” through remodeling immunosuppressive microenvironment, hypoxia microenvironment, and angiogenesis/lymphangiogenesis, and ECM are also reversed when treated by TCM.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Authors’ Contribution

Jingnan Xu, Zhuo Song, and Qiujun Guo contributed equally to this work and should be considered as co-first authors.

Acknowledgment

This work was supported by National Natural Science Foundation of China (nos. 81072802, 81273946, and 81473463).

References

F. Seretis, C. Seretis, H. Youssef, and M. Chapman, “Colorectal cancer: seed and soil hypothesis revisited,” Anticancer Research, vol. 34, no. 5, pp. 2087–2094, 2014.
View at: Google Scholar
I. J. Fidler, “The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited,” Nature Reviews Cancer, vol. 3, no. 6, pp. 453–458, 2003.
View at: Publisher Site | Google Scholar
J. Diao, J. Zhao, E. Winter, and M. S. Cattral, “Tumors suppress in situ proliferation of cytotoxic T cells by promoting differentiation of Gr-1⁺ conventional dendritic cells through IL-6,” The Journal of Immunology, vol. 186, no. 9, pp. 5058–5067, 2011.
View at: Publisher Site | Google Scholar
O. Oluwadara, L. Giacomelli, X. Brant et al., “The role of the microenvironment in tumor immune surveillance,” Bioinformation, vol. 5, no. 7, pp. 285–290, 2011.
View at: Publisher Site | Google Scholar
S. Chabot, N. Jabrane-Ferrat, K. Bigot et al., “A novel antiangiogenic and vascular normalization therapy targeted against human CD160 receptor,” The Journal of Experimental Medicine, vol. 208, no. 5, pp. 973–986, 2011.
View at: Publisher Site | Google Scholar
E. T. Shinohara and A. Maity, “Increasing sensitivity to radiotherapy and chemotherapy by using novel biological agents that alter the tumor microenvironment,” Current Molecular Medicine, vol. 9, no. 9, pp. 1034–1045, 2009.
View at: Publisher Site | Google Scholar
P. Lu, W. Su, Z.-H. Miao, H.-R. Niu, J. Liu, and Q.-L. Hua, “Effect and mechanism of ginsenoside Rg3 on postoperative life span of patients with non-small cell lung cancer,” Chinese Journal of Integrative Medicine, vol. 14, no. 1, pp. 33–36, 2008.
View at: Publisher Site | Google Scholar
B. Wang and J. Cui, “Treatment of mid-late stage NSCLC using sodium cantharidinate/vitamin B6/GP regimen in clinic,” Journal of Cancer Research and Therapeutics, vol. 10, no. 5, pp. 79–81, 2014.
View at: Publisher Site | Google Scholar
L. Guo, S.-P. Bai, L. Zhao, and X.-H. Wang, “Astragalus polysaccharide injection integrated with vinorelbine and cisplatin for patients with advanced non-small cell lung cancer: effects on quality of life and survival,” Medical Oncology, vol. 29, no. 3, pp. 1656–1662, 2012.
View at: Publisher Site | Google Scholar
L. W. Ruan and Y. C. Deng, “Study on effect of Xiaoaiping in enhancing efficacy of neoadjuvant chemotherapy for breast cancer and its mechanism,” Zhongguo Zhong Yao Za Zhi, vol. 40, no. 4, pp. 749–752, 2015.
View at: Google Scholar
Y. Liu, Z. W. Jia, L. Dong, R. Wang, and G. Q. Qiu, “A randomized pilot study of atractylenolide I on gastric cancer cachexia patients,” Evidence-Based Complementary and Alternative Medicine, vol. 5, no. 3, pp. 337–344, 2008.
View at: Publisher Site | Google Scholar
C. Zhong, H.-D. Li, D.-Y. Liu et al., “Clinical study of hepatectomy combined with Jianpi Huayu Therapy for hepatocellular carcinoma,” Asian Pacific Journal of Cancer Prevention, vol. 15, no. 14, pp. 5951–5957, 2014.
View at: Publisher Site | Google Scholar
T.-J. Qin, X.-H. Zhao, J. Yun, L.-X. Zhang, Z.-P. Ruan, and B.-R. Pan, “Efficacy and safety of gemcitabine-oxaliplatin combined with huachansu in patients with advanced gallbladder carcinoma,” World Journal of Gastroenterology, vol. 14, no. 33, pp. 5210–5216, 2008.
View at: Publisher Site | Google Scholar
M. I. James, C. Iwuji, G. Irving et al., “Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy,” Cancer Letters, vol. 364, no. 2, pp. 135–141, 2015.
View at: Publisher Site | Google Scholar
D.-R. Lu, D.-Y. Li, X.-Y. Chen, P.-Z. Ye, and S.-D. Tian, “Clinical research of compound Zhebei granules for increasing the therapeutic effect of chemotherapy in refractory acute leukemia patients,” Journal of Traditional Chinese Medicine, vol. 29, no. 3, pp. 190–194, 2009.
View at: Publisher Site | Google Scholar
Y. Jia, Q. Guan, Y. Guo, and C. Du, “Reduction of inflammatory hyperplasia in the intestine in colon cancer-prone mice by water-extract of Cistanche deserticola,” Phytotherapy Research, vol. 26, no. 6, pp. 812–819, 2012.
View at: Publisher Site | Google Scholar
Y. Sun, “Translational horizons in the tumor microenvironment: harnessing breakthroughs and targeting cures,” Medicinal Research Reviews, vol. 35, no. 2, pp. 408–436, 2015.
View at: Publisher Site | Google Scholar
J. Li, L. Li, R. Liu, and H.-S. Lin, “Establishing Chinese medicine characteristic tumor response evaluation system is the key to promote internationalization of Chinese medicine oncology,” Chinese Journal of Integrative Medicine, vol. 18, no. 10, pp. 730–736, 2012.
View at: Publisher Site | Google Scholar
M. W. Pickup, J. K. Mouw, and V. M. Weaver, “The extracellular matrix modulates the hallmarks of cancer,” EMBO Reports, vol. 15, no. 12, pp. 1243–1253, 2014.
View at: Publisher Site | Google Scholar
P. Lu, V. M. Weaver, and Z. Werb, “The extracellular matrix: a dynamic niche in cancer progression,” The Journal of Cell Biology, vol. 196, no. 4, pp. 395–406, 2012.
View at: Publisher Site | Google Scholar
M. Giussani, G. Merlino, V. Cappelletti, E. Tagliabue, and M. G. Daidone, “Tumor-extracellular matrix interactions: identification of tools associated with breast cancer progression,” Seminars in Cancer Biology, vol. 35, pp. 3–10, 2015.
View at: Publisher Site | Google Scholar
A. W. Holle, J. L. Young, and J. P. Spatz, “In vitro cancer cell-ECM interactions inform in vivo cancer treatment,” Advanced Drug Delivery Reviews, vol. 97, pp. 270–279, 2016.
View at: Publisher Site | Google Scholar
C. A. Sherman-Baust, A. T. Weeraratna, L. B. A. Rangel et al., “Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells,” Cancer Cell, vol. 3, no. 4, pp. 377–386, 2003.
View at: Publisher Site | Google Scholar
W. Deng, H. Sui, Q. Wang et al., “A Chinese herbal formula, Yi-Qi-Fu-Sheng, inhibits migration/invasion of colorectal cancer by down-regulating MMP-2/9 via inhibiting the activation of ERK/MAPK signaling pathways,” BMC Complementary and Alternative Medicine, vol. 13, article 65, 2013.
View at: Publisher Site | Google Scholar
R. Zhou, L. Xu, M. Ye, M. Liao, H. Du, and H. Chen, “Formononetin inhibits migration and invasion of MDA-MB-231 and 4T1 breast cancer cells by suppressing MMP-2 and MMP-9 through PI3K/AKT signaling pathways,” Hormone and Metabolic Research, vol. 46, no. 11, pp. 753–760, 2014.
View at: Publisher Site | Google Scholar
L. Zheng, Y.-M. Zhang, Y.-Z. Zhan, and C.-X. Liu, “Momordica cochinchinensis seed extracts suppress migration and invasion of human breast cancer ZR-75-30 cells via down-regulating MMP-2 and MMP-9,” Asian Pacific Journal of Cancer Prevention, vol. 15, no. 3, pp. 1105–1110, 2014.
View at: Publisher Site | Google Scholar
G. Kroemer, G. Mariño, and B. Levine, “Autophagy and the integrated stress response,” Molecular Cell, vol. 40, no. 2, pp. 280–293, 2010.
View at: Publisher Site | Google Scholar
P. Vaupel, M. Höckel, and A. Mayer, “Detection and characterization of tumor hypoxia using pO₂ histography,” Antioxidants and Redox Signaling, vol. 9, no. 8, pp. 1221–1235, 2007.
View at: Publisher Site | Google Scholar
J. L. Yu, J. W. Rak, B. L. Coomber, D. J. Hicklin, and R. S. Kerbel, “Effect of p53 status on tumor response to antiangiogenic therapy,” Science, vol. 295, no. 5559, pp. 1526–1528, 2002.
View at: Publisher Site | Google Scholar
X. Yang, D.-D. Yu, F. Yan et al., “The role of autophagy induced by tumor microenvironment in different cells and stages of cancer,” Cell & Bioscience, vol. 5, article 14, 2015.
View at: Publisher Site | Google Scholar
Z. Zhou, H. Liu, X. Chi et al., “A protein-corona-free $T_{1} – T_{2}$ dual-modal contrast agent for accurate imaging of lymphatic tumor metastasis,” ACS Applied Materials & Interfaces, vol. 7, no. 51, pp. 28286–28293, 2015.
View at: Publisher Site | Google Scholar
R. Kalluri and R. A. Weinberg, “The basics of epithelial-mesenchymal transition,” The Journal of Clinical Investigation, vol. 119, no. 6, pp. 1420–1428, 2009.
View at: Publisher Site | Google Scholar
Y. Lv, S. Zhao, J. Han, L. Zheng, Z. Yang, and L. Zhao, “Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer,” OncoTargets and Therapy, vol. 8, pp. 1941–1948, 2015.
View at: Publisher Site | Google Scholar
E. A. Turley, M. Veiseh, D. C. Radisky, and M. J. Bissell, “Mechanisms of disease: epithelial-mesenchymal transition—does cellular plasticity fuel neoplastic progression?” Nature Clinical Practice Oncology, vol. 5, no. 5, pp. 280–290, 2008.
View at: Publisher Site | Google Scholar
H. Chen, A. Shen, Y. Zhang et al., “Pien Tze Huang inhibits hypoxia-induced epithelial-mesenchymal transition in human colon carcinoma cells through suppression of the HIF-1 pathway,” Experimental and Therapeutic Medicine, vol. 7, no. 5, pp. 1237–1242, 2014.
View at: Publisher Site | Google Scholar
Q. Dai, Q. Yin, L. Wei et al., “Oroxylin A regulates glucose metabolism in response to hypoxic stress with the involvement of Hypoxia-inducible factor-1 in human hepatoma HepG2 cells,” Molecular Carcinogenesis, 2015.
View at: Publisher Site | Google Scholar
K. Zhao, X. Song, Y. Huang et al., “Wogonin inhibits LPS-induced tumor angiogenesis via suppressing PI3K/Akt/NF-κB signaling,” European Journal of Pharmacology, vol. 737, pp. 57–69, 2014.
View at: Publisher Site | Google Scholar
H. Wang, L. Zhao, L.-T. Zhu et al., “Wogonin reverses hypoxia resistance of human colon cancer HCT116 cells via downregulation of HIF-1α and glycolysis, by inhibiting PI3K/Akt signaling pathway,” Molecular Carcinogenesis, vol. 53, no. 1, pp. E107–E118, 2014.
View at: Publisher Site | Google Scholar
G. Bellone, A. Carbone, C. Smirne et al., “Cooperative induction of a tolerogenic dendritic cell phenotype by cytokines secreted by pancreatic carcinoma cells,” The Journal of Immunology, vol. 177, no. 5, pp. 3448–3460, 2006.
View at: Publisher Site | Google Scholar
B.-N. Lee, M. Follen, G. Rodriquez et al., “Deficiencies in myeloid antigen-presenting cells in women with cervical squamous intraepithelial lesions,” Cancer, vol. 107, no. 5, pp. 999–1007, 2006.
View at: Publisher Site | Google Scholar
I. Perrot, D. Blanchard, N. Freymond et al., “Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage,” The Journal of Immunology, vol. 178, no. 5, pp. 2763–2769, 2007.
View at: Publisher Site | Google Scholar
L. A. Ormandy, A. Färber, T. Cantz et al., “Direct ex vivo analysis of dendritic cells in patients with hepatocellular carcinoma,” World Journal of Gastroenterology, vol. 12, no. 20, pp. 3275–3282, 2006.
View at: Google Scholar
D. Gabrilovich, “Mechanisms and functional significance of tumour-induced dendritic-cell defects,” Nature Reviews Immunology, vol. 4, no. 12, pp. 941–952, 2004.
View at: Publisher Site | Google Scholar
Y. Tian, X. Li, H. Li, Q. Lu, G. Sun, and H. Chen, “Astragalus mongholicus regulate the Toll-like-receptor 4 meditated signal transduction of dendritic cells to restrain stomach cancer cells,” African Journal of Traditional, Complementary and Alternative Medicines, vol. 11, no. 3, pp. 92–96, 2014.
View at: Publisher Site | Google Scholar
J. E. Talmadge and D. I. Gabrilovich, “History of myeloid-derived suppressor cells,” Nature Reviews Cancer, vol. 13, no. 10, pp. 739–752, 2013.
View at: Publisher Site | Google Scholar
G. Schiavoni, L. Gabriele, and F. Mattei, “The tumor microenvironment: a pitch for multiple players,” Frontiers in Oncology, vol. 3, article 90, 2013.
View at: Publisher Site | Google Scholar
R. Wang, Y. Li, W. Wang, M. Zhou, and Z. Cao, “Compound K suppresses myeloid-derived suppressor cells in a mouse model bearing CT26 colorectal cancer xenograft,” Nan Fang Yi Ke Da Xue Xue Bao, vol. 35, no. 5, pp. 748–752, 2015.
View at: Google Scholar
B. Ruffell, N. I. Affara, and L. M. Coussens, “Differential macrophage programming in the tumor microenvironment,” Trends in Immunology, vol. 33, no. 3, pp. 119–126, 2012.
View at: Publisher Site | Google Scholar
B.-Z. Qian and J. W. Pollard, “Macrophage diversity enhances tumor progression and metastasis,” Cell, vol. 141, no. 1, pp. 39–51, 2010.
View at: Publisher Site | Google Scholar
J. W. Pollard, “Trophic macrophages in development and disease,” Nature Reviews Immunology, vol. 9, no. 4, pp. 259–270, 2009.
View at: Publisher Site | Google Scholar
G. Solinas, G. Germano, A. Mantovani, and P. Allavena, “Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation,” Journal of Leukocyte Biology, vol. 86, no. 5, pp. 1065–1073, 2009.
View at: Publisher Site | Google Scholar
S. F. Schoppmann, P. Birner, J. Stöckl et al., “Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis,” The American Journal of Pathology, vol. 161, no. 3, pp. 947–956, 2002.
View at: Publisher Site | Google Scholar
H. Y. Tan, N. Wang, K. Man, S. W. Tsao, C. M. Che, and Y. Feng, “Autophagy-induced RelB/p52 activation mediates tumour-associated macrophage repolarisation and suppression of hepatocellular carcinoma by natural compound baicalin,” Cell Death & Disease, vol. 6, no. 10, Article ID e1942, 2015.
View at: Publisher Site | Google Scholar
S.-Q. Gong, W. Sun, M. Wang, and Y.-Y. Fu, “Role of TLR4 and TCR or BCR against baicalin-induced responses in T and B cells,” International Immunopharmacology, vol. 11, no. 12, pp. 2176–2180, 2011.
View at: Publisher Site | Google Scholar
X. Qi, G. Liu, L. Qiu, X. Lin, and M. Liu, “Marine bromophenol bis(2,3-dibromo-4,5-dihydroxybenzyl) ether, represses angiogenesis in HUVEC cells and in zebrafish embryos via inhibiting the VEGF signal systems,” Biomedicine & Pharmacotherapy, vol. 75, pp. 58–66, 2015.
View at: Publisher Site | Google Scholar
Y.-C. Hseu, S.-C. Chen, W.-H. Lin et al., “Toona sinensis (leaf extracts) inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis in vascular endothelial cells,” Journal of Ethnopharmacology, vol. 134, no. 1, pp. 111–121, 2011.
View at: Publisher Site | Google Scholar
N. Ferrara, “Vascular endothelial growth factor: basic science and clinical progress,” Endocrine Reviews, vol. 25, no. 4, pp. 581–611, 2004.
View at: Publisher Site | Google Scholar
C. I. M. Baeten, F. Hillen, P. Pauwels, A. P. de Bruine, and C. G. M. I. Baeten, “Prognostic role of vasculogenic mimicry in colorectal cancer,” Diseases of the Colon and Rectum, vol. 52, no. 12, pp. 2028–2035, 2009.
View at: Publisher Site | Google Scholar
B. Sun, S. Zhang, D. Zhang et al., “Vasculogenic mimicry is associated with high tumor grade, invasion and metastasis, and short survival in patients with hepatocellular carcinoma,” Oncology Reports, vol. 16, no. 4, pp. 693–698, 2006.
View at: Google Scholar
M. Li, Y. Gu, Z. Zhang et al., “Vasculogenic mimicry: a new prognostic sign of gastric adenocarcinoma,” Pathology and Oncology Research, vol. 16, no. 2, pp. 259–266, 2010.
View at: Publisher Site | Google Scholar
J.-M. Lü, Q. Yao, and C. Chen, “Ginseng compounds: an update on their molecular mechanisms and medical applications,” Current Vascular Pharmacology, vol. 7, no. 3, pp. 293–302, 2009.
View at: Publisher Site | Google Scholar
D. F. Zeng, J. L. Wang, P. Y. Kong, C. Chang, J. Li, and J. Li, “Ginsenoside Rg3 inhibits HIF-1α and VEGF expression in patient with acute leukemia via inhibiting the activation of PI3K/Akt and ERK1/2 pathways,” International Journal of Clinical and Experimental Pathology, vol. 7, no. 5, pp. 2172–2178, 2014.
View at: Google Scholar
N. Koonrungsesomboon, K. Na-Bangchang, and J. Karbwang, “Therapeutic potential and pharmacological activities of Atractylodes lancea (Thunb.) DC,” Asian Pacific Journal of Tropical Medicine, vol. 7, no. 6, pp. 421–428, 2014.
View at: Publisher Site | Google Scholar
S. Wang, R. Cai, J. Ma et al., “The natural compound codonolactone impairs tumor induced angiogenesis by downregulating BMP signaling in endothelial cells,” Phytomedicine, vol. 22, no. 11, pp. 1017–1026, 2015.
View at: Publisher Site | Google Scholar
J.-M. Lin, L.-H. Wei, Y.-Q. Chen et al., “Pien Tze Huang (片仔癀)-induced apoptosis in human colon cancer HT-29 cells is associated with regulation of the Bcl-2 family and activation of caspase 3,” Chinese Journal of Integrative Medicine, vol. 17, no. 9, pp. 685–690, 2011.
View at: Publisher Site | Google Scholar
Q. Zhuang, F. Hong, A. Shen et al., “Pien Tze Huang inhibits tumor cell proliferation and promotes apoptosis via suppressing the STAT3 pathway in a colorectal cancer mouse model,” International Journal of Oncology, vol. 40, no. 5, pp. 1569–1574, 2012.
View at: Publisher Site | Google Scholar
A.-L. Shen, F. Hong, L.-Y. Liu et al., “Effects of Pien Tze Huang on angiogenesis in vivo and in vitro,” Chinese Journal of Integrative Medicine, vol. 18, no. 6, pp. 431–436, 2012.
View at: Publisher Site | Google Scholar
A. Shen, F. Hong, L. Liu et al., “Pien Tze Huang inhibits the proliferation of human colon carcinoma cells by arresting G1/S cell cycle progression,” Oncology Letters, vol. 4, no. 4, pp. 767–770, 2012.
View at: Publisher Site | Google Scholar
A. Shen, J. Lin, Y. Chen et al., “Pien Tze Huang inhibits tumor angiogenesis in a mouse model of colorectal cancer via suppression of multiple cellular pathways,” Oncology Reports, vol. 30, no. 4, pp. 1701–1706, 2013.
View at: Publisher Site | Google Scholar
A. Shen, Y. Chen, F. Hong et al., “Pien Tze Huang suppresses IL-6-inducible STAT3 activation in human colon carcinoma cells through induction of SOCS3,” Oncology Reports, vol. 28, no. 6, pp. 2125–2130, 2012.
View at: Publisher Site | Google Scholar
G. W. Yang, J. S. Jiang, and W. Q. Lu, “Ferulic acid exerts anti-angiogenic and anti-tumor activity by targeting fibroblast growth factor receptor 1-mediated angiogenesis,” International Journal of Molecular Sciences, vol. 16, no. 10, pp. 24011–24031, 2015.
View at: Publisher Site | Google Scholar
W. Zheng, A. Aspelund, and K. Alitalo, “Lymphangiogenic factors, mechanisms, and applications,” The Journal of Clinical Investigation, vol. 124, no. 3, pp. 878–887, 2014.
View at: Publisher Site | Google Scholar
S. Karaman and M. Detmar, “Mechanisms of lymphatic metastasis,” The Journal of Clinical Investigation, vol. 124, no. 3, pp. 922–928, 2014.
View at: Publisher Site | Google Scholar
X. Kang, J. Kim, M. Deng et al., “Inhibitory leukocyte immunoglobulin-like receptors: immune checkpoint proteins and tumor sustaining factors,” Cell Cycle, vol. 15, no. 1, pp. 25–40, 2016.
View at: Publisher Site | Google Scholar
Y. Kimura and M. Sumiyoshi, “Anti-tumor and anti-metastatic actions of wogonin isolated from Scutellaria baicalensis roots through anti-lymphangiogenesis,” Phytomedicine, vol. 20, no. 3-4, pp. 328–336, 2013.
View at: Publisher Site | Google Scholar
Y.-Z. Fan, J.-Y. Fu, Z.-M. Zhao, and C.-Q. Chen, “Inhibitory effect of norcantharidin on the growth of human gallbladder carcinoma GBC-SD cells in vitro,” Hepatobiliary & Pancreatic Diseases International, vol. 6, no. 1, pp. 72–80, 2007.
View at: Google Scholar
Y.-Z. Fan, Z.-M. Zhao, J.-Y. Fu, C.-Q. Chen, and W. Sun, “Norcantharidin inhibits growth of human gallbladder carcinoma xenografted tumors in nude mice by inducing apoptosis and blocking the cell cycle in vivo,” Hepatobiliary & Pancreatic Diseases International, vol. 9, no. 4, pp. 414–422, 2010.
View at: Google Scholar
C.-C. Yu, F.-Y. Ko, C.-S. Yu et al., “Norcantharidin triggers cell death and DNA damage through S-phase arrest and ROS-modulated apoptotic pathways in TSGH 8301 human urinary bladder carcinoma cells,” International Journal of Oncology, vol. 41, no. 3, pp. 1050–1060, 2012.
View at: Publisher Site | Google Scholar
S.-H. Kok, S.-J. Cheng, C.-Y. Hong et al., “Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio,” Cancer Letters, vol. 217, no. 1, pp. 43–52, 2005.
View at: Publisher Site | Google Scholar
Y.-P. Ho, K. K. W. To, S. C. F. Au-Yeung, X. Wang, G. Lin, and X. Han, “Potential new antitumor agents from an innovative combination of demethylcantharidin, a modified traditional chinese medicine, with a platinum moiety,” Journal of Medicinal Chemistry, vol. 44, no. 13, pp. 2065–2068, 2001.
View at: Publisher Site | Google Scholar
J. A. Nagy, E. Vasile, D. Feng et al., “Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis,” The Journal of Experimental Medicine, vol. 196, no. 11, pp. 1497–1506, 2002.
View at: Publisher Site | Google Scholar
F. Räßler, U. Voigt, S. Metz, P. Elsner, and S. Schliemann, “Fast-growing tumor of the eyelid,” Journal der Deutschen Dermatologischen Gesellschaft, vol. 14, no. 1, pp. 81–84, 2016.
View at: Publisher Site | Google Scholar
D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011.
View at: Publisher Site | Google Scholar
V. Catalano, A. Turdo, S. Di Franco, F. Dieli, M. Todaro, and G. Stassi, “Tumor and its microenvironment: a synergistic interplay,” Seminars in Cancer Biology, vol. 23, no. 6, pp. 522–532, 2013.
View at: Publisher Site | Google Scholar
S. Wang, X. Wu, M. Tan et al., “Fighting fire with fire: poisonous Chinese herbal medicine for cancer therapy,” Journal of Ethnopharmacology, vol. 140, no. 1, pp. 33–45, 2012.
View at: Publisher Site | Google Scholar
F. He, H.-N. Wu, M.-Y. Cai et al., “Inhibition of ovarian cancer cell proliferation by Pien Tze Huang via the AKT-mTOR pathway,” Oncology Letters, vol. 7, no. 6, pp. 2047–2052, 2014.
View at: Publisher Site | Google Scholar
E. Hervouet, M. Cheray, F. M. Vallette, and P. Cartron, “DNA methylation and apoptosis resistance in cancer cells,” Cells, vol. 2, no. 3, pp. 545–573, 2013.
View at: Publisher Site | Google Scholar
C.-M. Hsu, Y. Tsai, L. Wan, and F.-J. Tsai, “Bufalin induces G2/M phase arrest and triggers autophagy via the TNF, JNK, BECN-1 and ATG8 pathway in human hepatoma cells,” International Journal of Oncology, vol. 43, no. 1, pp. 338–348, 2013.
View at: Publisher Site | Google Scholar
B. Wang, Q. Han, and Y. Zhu, “Oxymatrine inhibited cell proliferation by inducing apoptosis in human lung cancer A549 cells,” Bio-Medical Materials and Engineering, vol. 26, pp. S165–S172, 2015.
View at: Publisher Site | Google Scholar
D. A. Liebermann, B. Hoffman, and D. Vesely, “p53 induced growth arrest versus apoptosis and its modulation by survival cytokines,” Cell Cycle, vol. 6, no. 2, pp. 166–170, 2007.
View at: Publisher Site | Google Scholar
F. Liu, J.-G. Wang, S.-Y. Wang, Y. Li, Y.-P. Wu, and S.-M. Xi, “Antitumor effect and mechanism of Gecko on human esophageal carcinoma cell lines in vitro and xenografted sarcoma 180 in Kunming mice,” World Journal of Gastroenterology, vol. 14, no. 25, pp. 3990–3996, 2008.
View at: Publisher Site | Google Scholar
L. Ma and W. Li, “Emodin inhibits LOVO colorectal cancer cell proliferation via the regulation of the Bcl-2/Bax ratio and cytochrome c,” Experimental and Therapeutic Medicine, vol. 8, no. 4, pp. 1225–1228, 2014.
View at: Publisher Site | Google Scholar
R. M. Mohammad, I. Muqbil, L. Lowe et al., “Broad targeting of resistance to apoptosis in cancer,” Seminars in Cancer Biology, vol. 35, supplement, pp. S78–S103, 2015.
View at: Google Scholar
P. Plastina, D. Bonofiglio, D. Vizza et al., “Identification of bioactive constituents of Ziziphus jujube fruit extracts exerting antiproliferative and apoptotic effects in human breast cancer cells,” Journal of Ethnopharmacology, vol. 140, no. 2, pp. 325–332, 2012.
View at: Publisher Site | Google Scholar
B. Wang, Q. Han, and Y. Zhu, “Oxymatrine inhibited cell proliferation by inducing apoptosis in human lung cancer A549 cells,” Bio-Medical Materials and Engineering, vol. 26, supplement 1, pp. S165–S172, 2015.
View at: Publisher Site | Google Scholar
L. Chu, H. Zhao, J. Fang et al., “The traditional Chinese medicinal formula BDL301 suppresses tumor growth by inhibiting STAT3 pathway and inducing apoptosis in colorectal cancer cells,” DNA and Cell Biology, vol. 34, no. 3, pp. 178–188, 2015.
View at: Publisher Site | Google Scholar
X.-Y. Dang, L. Dong, H.-T. Shi, and B.-C. Zou, “Effects of serum containing Chinese medicine Sanpi Pingwei (散癖平胃) formula on proliferation and apoptosis of human SGC-7901 cells,” Chinese Journal of Integrative Medicine, vol. 19, no. 2, pp. 119–126, 2013.
View at: Publisher Site | Google Scholar
N. Li, D. Zheng, J. Xue et al., “Cidan inhibits liver cancer cell growth by reducing COX-2 and VEGF expression and cell cycle arrest,” Experimental and Therapeutic Medicine, vol. 9, no. 5, pp. 1709–1718, 2015.
View at: Publisher Site | Google Scholar
W. Liu, S. Y. Li, X. E. Huang, J. J. Cui, T. Zhao, and H. Zhang, “Inhibition of tumor growth in vitro by a combination of extracts from Rosa roxburghii Tratt and Fagopyrum cymosum,” Asian Pacific Journal of Cancer Prevention, vol. 13, no. 5, pp. 2409–2414, 2012.
View at: Publisher Site | Google Scholar
Y.-L. Hsu, M.-H. Yen, P.-L. Kuo et al., “San-Zhong-Kui-Jian-Tang, a traditional Chinese medicine prescription, inhibits the proliferation of human breast cancer cell by blocking cell cycle progression and inducing apoptosis,” Biological & Pharmaceutical Bulletin, vol. 29, no. 12, pp. 2388–2394, 2006.
View at: Publisher Site | Google Scholar
X. S. Chai, X. X. Zhang, and W. Y. Wu, “Xiaoji Decoction inhibited cell proliferation and induced apoptosis through Akt signaling pathway in human lung cancer A549 cells,” Chinese Journal of Integrative Medicine, vol. 20, no. 9, pp. 701–705, 2014.
View at: Publisher Site | Google Scholar
S.-Y. Xi, Y.-H. Teng, Y. Chen et al., “Jianpi Huayu Decoction inhibits proliferation in human colorectal cancer cells (SW480) by inducing G0/G1-phase cell cycle arrest and apoptosis,” Evidence-Based Complementary and Alternative Medicine, vol. 2015, Article ID 236506, 8 pages, 2015.
View at: Publisher Site | Google Scholar
L. Zhang, W. Tian, S. Kim, W. Ding, Y. Tong, and S. Chen, “Arsenic sulfide, the main component of realgar, a traditional Chinese medicine, induces apoptosis of gastric cancer cells in vitro and in vivo,” Drug Design Development and Therapy, vol. 9, pp. 79–92, 2015.
View at: Publisher Site | Google Scholar
M. Qiao, S. Sheng, and A. B. Pardee, “Metastasis and AKT activation,” Cell Cycle, vol. 7, no. 19, pp. 2991–2996, 2008.
View at: Publisher Site | Google Scholar
J. K. Beatty, A. Bhargava, and A. G. Buret, “Post-infectious irritable bowel syndrome: mechanistic insights into chronic disturbances following enteric infection,” World Journal of Gastroenterology, vol. 20, no. 14, pp. 3976–3985, 2014.
View at: Publisher Site | Google Scholar
Z. Liu, Z. Liu, X. Zhang, P. Xue, and H. Zhang, “RY10-4 suppressed metastasis of MDA-MB-231 by stabilizing ECM and E-cadherin,” Biomedicine & Pharmacotherapy, vol. 68, no. 4, pp. 439–445, 2014.
View at: Publisher Site | Google Scholar
Y. Zhang, J. Liu, J. Kou, J. Yu, and B. Yu, “DT-13 suppresses MDA-MB-435 cell adhesion and invasion by inhibiting MMP-2/9 via the p38 MAPK pathway,” Molecular Medicine Reports, vol. 6, no. 5, pp. 1121–1125, 2012.
View at: Publisher Site | Google Scholar
X. Liu, R. Dong, Z. Jiang et al., “MDC1 promotes ovarian cancer metastasis by inducing epithelial-mesenchymal transition,” Tumor Biology, vol. 36, no. 6, pp. 4261–4269, 2015.
View at: Publisher Site | Google Scholar
M. S. Tretiakova, J. Hart, M. T. Shabani-Rad, J. Zhang, and Z.-H. Gao, “Distinction of hepatocellular adenoma from hepatocellular carcinoma with and without cirrhosis using E-cadherin and matrix metalloproteinase immunohistochemistry,” Modern Pathology, vol. 22, no. 8, pp. 1113–1120, 2009.
View at: Publisher Site | Google Scholar
M. Arechederra, N. Priego, A. Vázquez-Carballo et al., “p38 MAPK down-regulates fibulin 3 expression through methylation of gene regulatory sequences: role in migration and invasion,” The Journal of Biological Chemistry, vol. 290, no. 7, pp. 4383–4397, 2015.
View at: Publisher Site | Google Scholar
W. Li, C. Chen, S. M. Saud et al., “Fei-Liu-Ping ointment inhibits lung cancer growth and invasion by suppressing tumor inflammatory microenvironment,” BMC Complementary and Alternative Medicine, vol. 14, article 153, 2014.
View at: Publisher Site | Google Scholar
Y.-W. Chiu, T.-H. Lin, W.-S. Huang et al., “Baicalein inhibits the migration and invasive properties of human hepatoma cells,” Toxicology and Applied Pharmacology, vol. 255, no. 3, pp. 316–326, 2011.
View at: Publisher Site | Google Scholar
Y. Ohashi, Y. Tsuchiya, K. Koizumi, H. Sakurai, and I. Saiki, “Prevention of intrahepatic metastasis by curcumin in an orthotopic implantation model,” Oncology, vol. 65, no. 3, pp. 250–258, 2003.
View at: Publisher Site | Google Scholar
D. S. Vinay, E. P. Ryan, G. Pawelec et al., “Immune evasion in cancer: mechanistic basis and therapeutic strategies,” Seminars in Cancer Biology, vol. 35, supplement, pp. S185–S198, 2015.
View at: Publisher Site | Google Scholar
J. B. Swann and M. J. Smyth, “Immune surveillance of tumors,” The Journal of Clinical Investigation, vol. 117, no. 5, pp. 1137–1146, 2007.
View at: Publisher Site | Google Scholar
J. W. Shay and I. B. Roninson, “Hallmarks of senescence in carcinogenesis and cancer therapy,” Oncogene, vol. 23, no. 16, pp. 2919–2933, 2004.
View at: Publisher Site | Google Scholar
Q. Guo, J. Li, and H. Lin, “Effect and molecular mechanisms of traditional chinese medicine on regulating tumor immunosuppressive microenvironment,” BioMed Research International, vol. 2015, Article ID 261620, 12 pages, 2015.
View at: Publisher Site | Google Scholar
M. Campoli and S. Ferrone, “Tumor escape mechanisms: potential role of soluble HLA antigens and NK cells activating ligands,” Tissue Antigens, vol. 72, no. 4, pp. 321–334, 2008.
View at: Publisher Site | Google Scholar
Y.-L. Li, B.-G. Sun, T. Xiang, Z.-X. Chen, and S.-J. Zhang, “Effect of invigorating spleen and detoxification decoction on MHC I/MHC II in spleen-deficiency liver cancer rats survival,” Journal of Chinese Medicinal Materials, vol. 37, no. 3, pp. 454–460, 2014.
View at: Google Scholar
M. Villa-Morales and J. Fernández-Piqueras, “Targeting the Fas/FasL signaling pathway in cancer therapy,” Expert Opinion on Therapeutic Targets, vol. 16, no. 1, pp. 85–101, 2012.
View at: Publisher Site | Google Scholar
E. Reichmann, “The biological role of the Fas/FasL system during tumor formation and progression,” Seminars in Cancer Biology, vol. 12, no. 4, pp. 309–315, 2002.
View at: Publisher Site | Google Scholar
J. Li, G.-Z. Sun, H.-S. Lin et al., “The herb medicine formula ‘Yang Wei Kang Liu’ improves the survival of late stage gastric cancer patients and induces the apoptosis of human gastric cancer cell line through Fas/Fas ligand and Bax/Bcl-2 pathways,” International Immunopharmacology, vol. 8, no. 9, pp. 1196–1206, 2008.
View at: Publisher Site | Google Scholar
M. Kedmi, A. Avigdor, and A. Nagler, “Anti-PD-1-targeted therapies focusing on lymphatic malignancies: biological rationale, clinical challenges and opportunities,” Acta Haematologica, vol. 133, no. 2, pp. 129–135, 2014.
View at: Publisher Site | Google Scholar
M. E. Keir, M. J. Butte, G. J. Freeman, and A. H. Sharpe, “PD-1 and its ligands in tolerance and immunity,” Annual Review of Immunology, vol. 26, pp. 677–704, 2008.
View at: Publisher Site | Google Scholar
J. R. Wang, J. Y. Wang, T. T. Zhang, and X. D. Cheng, “Regulate molecular expression of PD-1/PD-Ls by Astragalus polysaccharides on melanoma mice,” Acta Universitatis Traditionis Medicalis Sinensis Pharmacologiaeque Shanghai, vol. 28, no. 5, pp. 74–79, 2014.
View at: Google Scholar
J. Gu, X. Fang, J. Hao, and X. Sha, “Reversal of P-glycoprotein-mediated multidrug resistance by CD44 antibody-targeted nanocomplexes for short hairpin RNA-encoding plasmid DNA delivery,” Biomaterials, vol. 45, pp. 99–114, 2015.
View at: Publisher Site | Google Scholar
J. C. Leighton Jr. and L. J. Goldstein, “P-glycoprotein in adult solid tumors: expression and prognostic significance,” Hematology/Oncology Clinics of North America, vol. 9, no. 2, pp. 251–273, 1995.
View at: Google Scholar
E. K. Fetisova, A. V. Avetisyan, D. S. Izyumov, M. V. Korotetskaya, B. V. Chernyak, and V. P. Skulachev, “Mitochondria-targeted antioxidant SkQR1 selectively protects MDR (Pgp 170)-negative cells against oxidative stress,” FEBS Letters, vol. 584, no. 3, pp. 562–566, 2010.
View at: Publisher Site | Google Scholar
W.-B. Li, Y. Li, C. Yu, and Y.-M. He, “Reversal of multidrug resistance by the Chinese medicine Yiqi Jianpi Huaji decoction and the mechanism of action in human gastric cancer SGC7901/VCR Cells,” Evidence-Based Complementary and Alternative Medicine, vol. 2015, Article ID 390812, 11 pages, 2015.
View at: Publisher Site | Google Scholar
S. Y. Eid, M. Z. El-Readi, M. L. Ashour, and M. Wink, “Fallopia japonica, a natural modulator, can overcome multidrug resistance in cancer cells,” Evidence-Based Complementary and Alternative Medicine, vol. 2015, Article ID 868424, 8 pages, 2015.
View at: Publisher Site | Google Scholar
F. Chen, M. Zhuang, C. Zhong et al., “Baicalein reverses hypoxia-induced 5-FU resistance in gastric cancer AGS cells through suppression of glycolysis and the PTEN/Akt/HIF-1α signaling pathway,” Oncology Reports, vol. 33, no. 1, pp. 457–463, 2015.
View at: Publisher Site | Google Scholar
H. Sui, L.-H. Zhou, Y.-L. Zhang et al., “Evodiamine suppresses ABCG2 mediated drug resistance by inhibiting p50/NF-κB pathway in colorectal cancer,” Journal of Cellular Biochemistry, 2015.
View at: Publisher Site | Google Scholar
C.-Z. Wang, X. Luo, B. Zhang et al., “Notoginseng enhances anti-cancer effect of 5-fluorouracil on human colorectal cancer cells,” Cancer Chemotherapy and Pharmacology, vol. 60, no. 1, pp. 69–79, 2007.
View at: Publisher Site | Google Scholar
J. M. Llovet, S. Ricci, V. Mazzaferro et al., “Sorafenib in advanced hepatocellular carcinoma,” The New England Journal of Medicine, vol. 359, no. 4, pp. 378–390, 2008.
View at: Publisher Site | Google Scholar
B. Zhai and X.-Y. Sun, “Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma,” World Journal of Hepatology, vol. 5, no. 7, pp. 345–352, 2013.
View at: Publisher Site | Google Scholar
B. Zhai, F. Hu, X. Jiang et al., “Inhibition of Akt reverses the acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular carcinoma,” Molecular Cancer Therapeutics, vol. 13, no. 6, pp. 1589–1598, 2014.
View at: Publisher Site | Google Scholar
B. Zhai, F. Hu, H. Yan et al., “Bufalin reverses resistance to sorafenib by inhibiting Akt activation in hepatocellular carcinoma: the role of endoplasmic reticulum stress,” PLoS ONE, vol. 10, no. 9, Article ID e0138485, 2015.
View at: Publisher Site | Google Scholar
M. F. Clarke, J. E. Dick, P. B. Dirks et al., “Cancer stem cells—perspectives on current status and future directions: AACR workshop on cancer stem cells,” Cancer Research, vol. 66, no. 19, pp. 9339–9344, 2006.
View at: Publisher Site | Google Scholar
Y.-C. He, F.-L. Zhou, Y. Shen, D.-F. Liao, and D. Cao, “Apoptotic death of cancer stem cells for cancer therapy,” International Journal of Molecular Sciences, vol. 15, no. 5, pp. 8335–8351, 2014.
View at: Publisher Site | Google Scholar
D. E. Costea, O. Tsinkalovsky, O. K. Vintermyr, A. C. Johannessen, and I. C. Mackenzie, “Cancer stem cells—new and potentially important targets for the therapy of oral squamous cell carcinoma,” Oral Diseases, vol. 12, no. 5, pp. 443–454, 2006.
View at: Publisher Site | Google Scholar
Y. Chang, Y. Zhao, H. Zhan, X. Wei, T. Liu, and B. Zheng, “Bufalin inhibits the differentiation and proliferation of human osteosarcoma cell line hMG63-derived cancer stem cells,” Tumor Biology, vol. 35, no. 2, pp. 1075–1082, 2014.
View at: Publisher Site | Google Scholar
E. R. Carlson, D. Oreadi, and J. M. McCoy, “Nevoid basal cell carcinoma syndrome and the keratocystic odontogenic tumor,” Journal of Oral and Maxillofacial Surgery, vol. 73, no. 12, pp. S77–S86, 2015.
View at: Publisher Site | Google Scholar
W. Li, Q. Wang, Q. Su et al., “Honokiol suppresses renal cancer cells' metastasis Via dual-blocking epithelial-mesenchymal transition and cancer stem cell properties through modulating miR-141/ZEB2 signaling,” Molecules and Cells, vol. 37, no. 5, pp. 383–388, 2014.
View at: Publisher Site | Google Scholar
L. Wei, P. Chen, Y. Chen et al., “Pien Tze Huang suppresses the stem-like side population in colorectal cancer cells,” Molecular Medicine Reports, vol. 9, no. 1, pp. 261–266, 2014.
View at: Publisher Site | Google Scholar
M. A. Swartz, N. Iida, E. W. Roberts et al., “Tumor microenvironment complexity: emerging roles in cancer therapy,” Cancer Research, vol. 72, no. 10, pp. 2473–2480, 2012.
View at: Publisher Site | Google Scholar
T. Yin, S. He, T. Ye, G. Shen, Y. Wan, and Y. Wang, “Antiangiogenic therapy using sunitinib combined with rapamycin retards tumor growth but promotes metastasis,” Translational Oncology, vol. 7, no. 2, pp. 221–229, 2014.
View at: Publisher Site | Google Scholar
C.-Y. Wu, L.-H. Yang, H.-Y. Yang et al., “Enhanced cancer radiotherapy through immunosuppressive stromal cell destruction in tumors,” Clinical Cancer Research, vol. 20, no. 3, pp. 644–657, 2014.
View at: Publisher Site | Google Scholar
C. M. Zegers, N. H. Rekers, D. H. Quaden et al., “Radiotherapy combined with the immunocytokine L19-IL2 provides long-lasting antitumor effects,” Clinical Cancer Research, vol. 21, no. 5, pp. 1151–1160, 2015.
View at: Publisher Site | Google Scholar
Q. Huang, F. Li, X. Liu et al., “Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy,” Nature Medicine, vol. 17, no. 7, pp. 860–866, 2011.
View at: Publisher Site | Google Scholar

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Copyright © 2016 Jingnan Xu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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