Molecular Biomarkers of Response to Antiangiogenic Therapy for Cancer
Box 2
Inflammatory molecules and their potential role in liver cancer angiogenesis. Abbreviations: AP-1, activator protein 1; C/EPB, CAAT/enhancer binding protein; CXCR, C- X-C-chemokine receptor; STAT, signal transducers and activators of transcription. Reproduced from [56].
Chronic inflammation is a potential precursor and promoter of carcinogenesis in many cancers [32–35].
In many cancers, nuclear factor kappa B (NF-B) is involved in tumor initiation and progression
mediated via STAT3 activation [36–38]. Inflammatory cytokines induced by NF-B pathway activation
might affect angiogenesis directly via endothelial cells, or indirectly by cancer cells or recruitment and/or
activation of inflammatory cells [39–46]. Interleukin (IL)-1α has a critical role
by recruitment of inflammatory cells [47, 48]. Tumor necrosis factor (TNF)-α can also promote tumor
progression by different pathways: direct effect on tumor cells, induction of CXCR4, and stimulation of
epithelial-mesenchymal transition [49]. TNF-α promotes cell survival and angiogenesis or induce
endothelial cell apoptosis, vascular disruption, and increased permeability. IL-6 is also induced
by activation of NF-B and other transcription factors (C/EPBb and AP-1) and modulates inflammation
via IL-6R and gp130. Vascular smooth muscle cells, Tlymphocytes, and macrophages secrete IL-6
to stimulate immune responses and promote inflammation. IL-6 may also have anti-inflammatory effects
by inhibition of TNF-α and IL-1, and activation of IL-1Ra and IL-10. The proliferative and survival effects of
IL-6 are mediated by STAT3 [34]. Moreover, IL-8 may have a role in cancer cell invasion [50, 51].
IL-8 can promote tumorigenesis and angiogenesis through CXCR1 and CXCR2, and the Duffy antigen
receptor for cytokines, which has no defined intracellular signaling capabilities [52]. Overexpression
of VEGF induces the expression of the CXCR4 ligand—stromal cell derived factor 1 alpha (SDF1α) or
CXCL12— and SDF1α and CXCR4 may drive cell migration and angiogenesis by VEGF-independent
mechanisms [53, 54]. Stem Cell Factor (also known as SCF or KIT-ligand) is a cytokine that binds to
the c-KIT receptor (CD117), primarily expressed by early hematopoietic precursors. While c-KIT
expression is rarely detectable in the cancer cells, both SCF and c-KIT could be expressed during
carcinogenesis, for example, in cholangiocarcinomas [55].
