Role of the microenvironment in tumor growth and in refractoriness/resistance to anti-angiogenic therapies
Introduction
Physiological angiogenesis, the formation of new blood vessels from the pre-existing vasculature, is a fundamental process in embryonic life that eventually results in the formation of a stable vasculature in the adult (Tang and Conti, 2004, Wilting and Christ, 1996). The normal microvessels are organized as highly ordered structures consisting of endothelial cells (ECs), mural cells (pericytes) and basement membrane. Pericytes are involved in vascular stabilization through establishment of contact with ECs along the length of the vessels and also through paracrine signaling (Hirschi and D’Amore, 1996). The basement membrane in the normal vasculature is a uniform and thin layer, enriched in type IV collagen, that covers almost the entire length of ECs (Rhodin and Fujita, 1989, Stingl and Rhodin, 1994). ECs line the vascular walls in a monolayer fashion and are quiescent in most of tissues and organs during the life of an individual. Therefore, angiogenesis is a relatively rare event in the adult, except in particular circumstances such as the cyclical growth of vessels in the ovarian corpus luteum (CL) (Ferrara et al., 1998) or during pregnancy (Torry et al., 2007). Postnatal vascularization may originate from proliferation, migration and remodeling of the ECs in the preexisting vasculature (Risau and Flamme, 1995).
The growth of new blood vessels under physiological or pathological conditions requires the concerted action of activators and inhibitors of angiogenesis. Activators of angiogenesis include vascular endothelial growth factor A (Ferrara and Henzel, 1989, Leung et al., 1989) (VEGF-A, hereafter VEGF), matrix metalloproteinases (MMPs) (Lafleur et al., 2003) such as MMP9 (Ahn and Brown, 2008, Vu et al., 1998), placenta growth factor (PlGF) (Maglione et al., 1991), fibroblast growth factor (FGF) (Fahmy et al., 2003) and hepatocyte growth factor (HGF) (Okada et al., 1999). Endogenous inhibitors of angiogenesis include thrombospondins (THSBs) (Rodriguez-Manzaneque et al., 2001) endostatin, angiostatin (O’Reilly, 1997, O’Reilly et al., 1997) and some of the interleukins such as IL-12 (Strasly et al., 2001). The balance between angiogenic activators and inhibitors is tilted in favor of activators of angiogenesis to allow formation of new blood vessels in tissue repair or in the development of the tumor vasculature (Folkman, 2004). Therefore, angiogenesis is a key process for tissue maintenance and homeostasis throughout the life of an individual.
Section snippets
Tumor angiogenesis as a therapeutic target
Besides normal development, vascular proliferation is important in pathophysiological processes such as tissue repair and regeneration or in growth and expansion of tumor cells (Ferrara and Kerbel, 2005, Folkman, 1971). Tumor vessels, however, are distinct relative to normal vasculature:
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They are disorganized and tortuous and their spatial distribution is significantly heterogeneous, resulting in lack of uniformity in drug distribution in the tumors (Eberhard et al., 2000). Tumor vessels do not
Inherent/acquired resistance to anti-angiogenic treatment
VEGF inhibitors have demonstrated clinical efficacy and a survival advantage in patients with advanced cancer, but most patients eventually relapse. Intensive studies are underway to elucidate cellular and molecular mechanisms underlying reduced response to anti-angiogenic agents in general and VEGF blockers in particular (Shojaei and Ferrara, 2008).
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Recent studies tested the hypothesis that increasing potency/affinity of anti-VEGF monoclonal antibody (Mab) may result in greater anti-tumor
Resistance to anti-angiogenic treatment and stromal cells
Reduced response to anti-VEGF may originate from tumor and/or non-tumor (stroma) compartments. In contrast to tumor cells, stromal cells are genetically stable and do not display chromosomal abnormalities (Hughes, 2008). The stroma comprises a heterogeneous population of cells including fibroblasts, pericytes, mesenchymal stem cells and hematopoietic cells. Stromal cells support tumor growth through several possible mechanisms such as direct contribution to tumor vasculature (Santarelli et al.,
Tumor-associated fibroblasts
Tumor associated fibroblasts (TAFs) are thought to be one of the major stromal elements implicated in tumor growth (Orimo and Weinberg, 2006). TAFs are enriched in PDGFR-α and are recruited to the tumors through gradient of PDGF-A and PDGF-C (Dong et al., 2004). A marked TAF infiltration has been reported in nude mice bearing the human lung carcinoma cell line CALU-6 (Tejada et al., 2006). A recent study by Liang et al. (2006) showed that blocking only human VEGF in xenografted tumors is not
Conclusion and perspectives
It is now established that targeting angiogenesis has clinical benefits in cancer patients (Kerbel, 2008). Furthermore, anti-angiogenic therapy has several attractive features such as broad applicability and a potential for combination with other anti-cancer agents.
Presently, a challenge is identifying predictive mouse models to investigate the mechanism of refractoriness and/or acquired resistance to antiangiogenic agents. It is unclear whether genetic models offer advantages over xenografts.
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