<i  >Background</i>. Mobilization of c-Kit<sup  >+</sup> hematopoietic cells (HCs) contributes to tumor vascularization. Whereas survival and proliferation of HCs are regulated by binding of the stem cell factor to its receptor c-Kit, migration of HCs is directed by stromal cell-derived factor (SDF)-1. Therefore, targeting migration of HCs provides a promising new strategy of anti-tumor therapy. <i  >Methods</i>. BALB/c mice (<svg style="vertical-align:-0.17555pt;width:42.912498px;" id="M1" height="11.0375" version="1.1" viewBox="0 0 42.912498 11.0375" width="42.912498"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,11.0375)">
		<g transform="translate(72,-63.17)">
			<text transform="matrix(1,0,0,-1,-71.95,63.4)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝑛</tspan>
				<tspan style="font-size: 12.50px; " x="9.6773224" y="0">=</tspan>
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				<tspan style="font-size: 12.50px; " x="27.969212" y="0">6</tspan>
			</text>

		</g>
	</g>
</svg>) were pretreated with an anti-c-Kit antibody followed by implantation of CT26.WT-GFP colorectal cancer cells into dorsal skinfold chambers. Animals (<svg style="vertical-align:-0.17555pt;width:35.099998px;" id="M2" height="10.9125" version="1.1" viewBox="0 0 35.099998 10.9125" width="35.099998"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,10.9125)">
		<g transform="translate(72,-63.27)">
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				<tspan style="font-size: 12.50px; " x="21.71771" y="0">8</tspan>
			</text>

		</g>
	</g>
</svg>) additionally received a neutralizing anti-SDF-1 antibody. Animals (<svg style="vertical-align:-0.17555pt;width:35.099998px;" id="M3" height="10.9125" version="1.1" viewBox="0 0 35.099998 10.9125" width="35.099998"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,10.9125)">
		<g transform="translate(72,-63.27)">
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			</text>

		</g>
	</g>
</svg>) treated with a control antibody served as controls. Investigations were performed using intravital fluorescence microscopy, immunohistochemistry, flow cytometry and western blot analysis. <i  >Results</i>. Blockade of c-Kit significantly enhanced tumor cell engraftment compared to controls due to stimulation of tumor cell proliferation and invasion without markedly affecting tumor vascularization. C-Kit blockade significantly increased VEGF and CXCR4 expression within the growing tumors. Neutralization of SDF-1 completely antagonized this anti-c-Kit-associated tumor growth by suppression of tumor neovascularization, inhibition of tumor cell proliferation and reduction of muscular infiltration. <i  >Conclusion</i>. Our study indicates that bone marrow suppression via anti-c-Kit pretreatment enhances tumor cell engraftment of colorectal metastases due to interaction with the SDF-1/CXCR4 pathway which is involved in HC-mediated tumor angiogenesis.

Kathrin Rupertus

Gudrun C. Y. Haberl

Claudia Scheuer

Michael D. Menger

Martin K. Schilling

Otto Kollmar

Bone Marrow Suppression by c-Kit Blockade Enhances Tumor Growth of Colorectal Metastases through the Action of Stromal Cell-Derived Factor-1

Between 2000 and 2050, the number of new cancer patients diagnosed annually is expected to double, with an accompanying increase in treatment costs of more than &#x24;80 billion over just the next decade. Efficacious strategies for cancer prevention will therefore be vital for improving patients&#39; quality of life and reducing healthcare costs. Judah Folkman first proposed antiangiogenesis as a strategy for preventing dormant microtumors from progressing to invasive cancer. Although antiangiogenic drugs are now available for many advanced malignancies (colorectal, lung, breast, kidney, liver, brain, thyroid, neuroendocrine, multiple myeloma, myelodysplastic syndrome), cost and toxicity considerations preclude their broad use for cancer prevention. Potent antiangiogenic molecules have now been identified in dietary sources, suggesting that a rationally designed antiangiogenic diet could provide a safe, widely available, and novel strategy for preventing cancer. This paper presents the scientific, epidemiologic, and clinical evidence supporting the role of an antiangiogenic diet for cancer prevention.

William W. Li

Vincent W. Li

Michelle Hutnik

Albert S. Chiou

Tumor Angiogenesis as a Target for Dietary Cancer Prevention

Inflammation is implicated in tumor development, invasion, and metastasis. Hence, it has been suggested that common cellular and molecular mechanisms are activated in wound repair and in cancer development. In addition, it has been previously proposed that the inflammatory response, which is associated with the wound healing process, could recapitulate ontogeny through the reexpression of the extraembryonic, that is, amniotic and vitelline, functions in the interstitial space of the injured tissue. If so, the use of inflammation by the cancer-initiating cell can also be supported in the ability to reacquire extraembryonic functional axes for tumor development, invasion, and metastasis. Thus, the diverse components of the tumor microenvironment could represent the overlapping reexpression of amniotic and vitelline functions. These functions would favor a gastrulation-like process, that is, the creation of a reactive stroma in which fibrogenesis and angiogenesis stand out.

Jose-Ignacio Arias

Maria-Angeles Aller

Isabel Prieto

Ana Arias

Zoe de Julian

Heping Yang

Jaime Arias

The Amazing Power of Cancer Cells to Recapitulate Extraembryonic Functions: The Cuckoo&#39;s Tricks

Despite recent advances in the management of ovarian cancer, it remains the most lethal gynecologic malignancy. Vascular endothelial growth factor (VEGF) has been shown to play a pivotal role in the progression of ovarian cancer leading to the eventual development of malignant ascites. On this basis, agents rendering VEGF ineffective by neutralizing VEGF (bevacizumab), blocking its receptors (aflibercept), or interfering with the postreceptor signaling pathways (sunitinib) provide us with the rational treatment options. These agents are generally used in combination with the standard chemotherapeutic drugs. Here, we discuss the basis of and the logic behind the use of these agents in the treatment of epithelial ovarian cancer, as well as their evaluation in different preclinical and clinical studies.

Afshin Amini

Samar Masoumi Moghaddam

David L. Morris

Mohammad H. Pourgholami

Utility of Vascular Endothelial Growth Factor Inhibitors in the Treatment of Ovarian Cancer: From Concept to Application

Physiological as well as pathological blood vessel formation are fundamentally dependent on cell-matrix interaction. Integrins, a family of major cell adhesion receptors, play a pivotal role in development, maintenance, and remodeling of the vasculature. Cell migration, invasion, and remodeling of the extracellular matrix (ECM) are integrin-regulated processes, and the expression of certain integrins also correlates with tumor progression. Recent advances in the understanding of how integrins are involved in the regulation of blood vessel formation and remodeling during tumor progression are highlighted. The increasing knowledge of integrin function at the molecular level, together with the growing repertoire of integrin inhibitors which allow their selective pharmacological manipulation, makes integrins suited as potential diagnostic markers and therapeutic targets.

Stephan Niland

Johannes A. Eble

Integrin-Mediated Cell-Matrix Interaction in Physiological and Pathological Blood Vessel Formation

Blood supply is crucial for rapid growth of a malignant tumor; medical imaging can play an important role in evaluating the vascular characterstics of tumors. Magnetic resonance imaging (MRI) and micro-computed tomography (CT) are able to detect tumors and measure blood volumes of microcirculation in tissue. In this study, we used MR imaging and micro-CT to assess the microcirculation in a VX2 tumor model in rabbits. MRI characterization was performed using the intravascular contrast agent Clariscan (NC100150-Injection); micro-CT with Microfil was used to directly depict blood vessels with diameters as low as 17&#x2009;um in tissue. Relative blood volume fraction (rBVF) in the tumor rim and blood vessel density (rBVD) over the whole tumor was calculated using the two imaging methods. Our study indicates that rBVF is negatively related to the volume of the tumor measured by ultrasound (<svg style="vertical-align:-0.27588pt;width:58.424999px;" id="M1" height="11.0375" version="1.1" viewBox="0 0 58.424999 11.0375" width="58.424999"  xmlns="http://www.w3.org/2000/svg">
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				<tspan style="font-size: 12.50px; " x="40.384689" y="0">0</tspan>
			</text>

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	</g>
</svg>). rBVF in the tissue of a VX2 tumor measured by MRI <i  >in vivo</i> was qualitatively consistent with the rBVD demonstrated by micro-CT <i  >in vitro</i> (<svg style="vertical-align:-0.27588pt;width:58.424999px;" id="M2" height="11.0375" version="1.1" viewBox="0 0 58.424999 11.0375" width="58.424999"  xmlns="http://www.w3.org/2000/svg">
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			</text>

		</g>
	</g>
</svg>). The good correlation between the two methods indicates that MRI studies are potentially valuable for assessing characteristics or tumor vascularity and for assessing response to therapy noninvasively.

X.-L. Qi

J. Liu

P. N. Burns

G. A. Wright

The Characteristics of Vascular Growth in VX2 Tumor Measured by MRI and Micro-CT

During the past 20 years, the phosphatase and tensin homolog PTEN has been shown to be involved in major physiological processes, and its mutation or loss is often associated with tumor formation. In addition PTEN regulates angiogenesis not only through its antagonizing effect on the PI3 kinase pathway mainly, but also through some phosphatase-independent functions. In this paper we delineate the role of this powerful tumor suppressor in tumor angiogenesis and dissect the underlying molecular mechanisms. Furthermore, it appears that, in a number of cancers, the PTEN status determines the response to chemotherapy, highlighting the need to monitor PTEN expression and to develop PTEN-targeted therapies.

Stéphane Rodriguez

Uyen Huynh-Do

The Role of PTEN in Tumor Angiogenesis

Acute myeloid leukemia (AML) arises from neoplastic transformation of hematopoietic stem and progenitor cells, and relapsed disease remains one of the greater challenges in treating this hematologic malignancy. This paper focuses on angiogenic aspects of AML including the significance and prognostic value of bone marrow microvessel density and circulating cytokine levels. We show three general mechanisms whereby AML exploits angiogenic pathways, including direct induction of angiogenesis, paracrine regulation, and autocrine stimulation. We also present early evidence that leukemia cells contribute directly to vascular endothelia. Novel treatment strategies are proposed, and a review of relevant antiangiogenic clinical trials is presented. By understanding how blood vessels can serve as a reservoir for refractory and relapsed AML, new diagnostics and promising treatment strategies can be developed.

Angelica Trujillo

Christie McGee

Christopher R. Cogle

Angiogenesis in Acute Myeloid Leukemia and Opportunities for Novel Therapies

Neuroblastoma, a progressive solid tumor in childhood, continues to be a clinical challenge. It is highly vascular, heterogeneous, and extracranial tumor that originates from neural crest. Angiogenesis, genetic abnormalities, and oncogene amplification are mainly responsible for malignant phenotype of this tumor. Survivability of malignant neuroblastoma patients remains poor despite the use of traditional therapeutic strategies. Angiogenesis is a very common and necessary pre-requisite for tumor progression and metastasis. Angiogenesis is also a major factor in making malignant neuroblastoma. Thus, prevention of angiogenesis can be a highly significant strategy in the treatment of malignant neuroblastoma. Here, we summarize our current understanding of angiogenesis in malignant neuroblstoma and describe the use of experimental anti-angiogenic agents either alone or in combination therapy. This review will clearly indicate the importance of angiogenesis in the pathogenesis of malignant neuroblastoma, its prevention as a promising therapy in preclinical models of malignant neuroblastoma, and prospective clinical trials.

Subhasree Roy Choudhury

Surajit Karmakar

Naren L. Banik

Swapan K. Ray

Targeting Angiogenesis for Controlling Neuroblastoma

Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established. Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors (colorectal cancer, renal cell carcinoma, and breast cancer) and multiple myeloma. Here we illustrate important aspects in the interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and summarize derived targeted therapies.

Fengjuan Fan

Alexander  Schimming

Dirk Jaeger

Klaus Podar

Targeting the Tumor Microenvironment: Focus on Angiogenesis

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<p><em>Journal of Oncology</em> publishes research related to breast cancer, lung cancer, gastrointestinal cancer, skin cancer, head and neck cancer, paediatric oncology, neurooncology as well as genitourinary cancer.</p>


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<p>Chief Editor, Professor Bruno Vincenzi, is an Associate Professor of Medical Oncology at University Campus Bio-Medico, Italy. His research interests include urogenital neoplasms and the pathophysiology and treatment of bone metastases.</p>


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Journal of Oncology publishes research related to breast cancer, lung cancer, gastrointestinal cancer, skin cancer, head and neck cancer, paediatric oncology, neurooncology as well as genitourinary cancer.

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Journal of Oncology

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