Pathways mediating VEGF-independent tumor angiogenesis

https://doi.org/10.1016/j.cytogfr.2009.11.003Get rights and content

Abstract

FDA approval of several inhibitors of the VEGF pathway has enabled significant advances in the therapy of cancer and neovascular age-related macular degeneration. However, similar to other therapies, inherent/acquired resistance to anti-angiogenic drugs may occur in patients, leading to disease progression. So far the lack of predictive biomarkers has precluded identification of patients most likely to respond to such treatments. Recent suggest that both tumor and non-tumor (stromal) cell types are involved in the reduced responsiveness to the treatments. The present review examines the role of tumor- as well as stromal cell-derived pathways involved in tumor growth and in refractoriness to anti-VEGF therapies.

Introduction

Angiogenesis is crucial for normal development. In embryonic life, the primary network of vascular endothelial cells is established by a process called vasculogenesis, followed by sprouting from preexisting endothelium and finally by remodeling of the network into mature vasculatures to create an efficient circulatory system [1], [2]. It is also well established that angiogenesis is implicated in a number of pathological processes [3]. Several angiogenic activators including members of the VEGF and FGF gene families (reviewed in [4], [5], [6]) and various inhibitors of angiogenesis such as thrombospondin, endostatin and tumstatin have been described [7]. In steady-state conditions, the balance between angiogenic activators and inhibitors results in very limited new blood vessel growth in the majority of tissues. However, the balance tilts in favor of the angiogenic stimulators in a variety of proliferative processes. It is now generally accepted that angiogenesis is a rate-limiting process in tumor growth [8], [9]. Without new blood vessels to supply nutrients and dispose of catabolic products, tumor cells could not sustain proliferation and thus are likely to remain dormant [10], [11]. Furthermore, much evidence links neovascularization with intraocular diseases resulting in blindness such as the wet form of age-related macular degeneration [12].

VEGF and its receptors represent one of the best-validated signaling pathways in angiogenesis [13]. Indeed, the current FDA approved anti-angiogenic agents inhibit the VEGF pathway. These agents include bevacizumab, a humanized anti-VEGF-A monoclonal antibody [14], and two small molecule inhibitors targeting VEGFR2 (in addition to other kinases), sorafenib and sunitinib [15], [16], [17], [18]. However, not all cancer patients benefit from such anti-angiogenic therapies, and some that do benefit initially might become less responsive during the treatment as well as showing some adverse effects [16], [18], [19]. Hence, there is an urgent need to elucidate the mechanisms that mediate resistance to anti-angiogenic agents.

Tumor cells have been traditionally thought to be the major sources of angiogenic factors [20]. However, much evidence now supports the notion that the stroma also contributes to tumorigenesis not only through secretion of cytokines that stimulate tumor cell proliferation and angiogenesis, but also by modulation of the immune system (reviewed in [21], [22], [23], [24], [25]).

This article will discuss our current understanding of both tumor- and stromal-derived molecular pathways mediating VEGF-independent tumor angiogenesis. In several cases, significant overlaps occur.

Section snippets

Tumor vessels are abnormal

Blood vessel proliferation is an essential physiological process [5], [26]. Sprouting is one of the major mechanisms of expansion in the network of vessels in the growing tumors through filopodia and endothelial stalk cells [27]. Tumor vessels are distinct in several respects relative to normal vasculature as they are disorganized and tortuous and their spatial distribution is significantly heterogeneous, resulting in uneven drug distribution in the tumors [28]. Tumor vessels do not follow the

Role of VEGF-A in angiogenesis

VEGF-A is one of the major regulators of both physiological and pathological angiogenesis [38]. VEGF is a member of a gene family that also includes VEGF-B, VEGF-C, VEGF-D and PlGF [1], [13], [39]. VEGF-A binds two tyrosine kinase receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) [13]. The importance of VEGF-A in the development of the vascular system is underscored by early embryonic lethality following inactivation of a single VEGF-A allele [40]. Several studies indicated that VEGF is highly

Resistance to anti-angiogenic therapies

In principle, at least some of the cellular and molecular mechanisms of resistance to anti-angiogenic compounds may be similar to those associated with cytotoxic agents [53]. For example, resistance to cytotoxic or anti-angiogenic agents may arise from a reduction in their bioavailability in the tumors or through upregulation of anti-apoptotic factors. Several mechanisms of inherent refractoriness or acquired resistance to anti-angiogenic agents have been identified in pre-clinical models

Members of the VEGF family

Various members of the VEGF gene family have been implicated in incomplete response to VEGF-A blockers. Placenta growth factor (PlGF), a member of VEGF family that binds specifically to VEGFR1 has received recently significant attention [69], [70]. VEGFR-1 is expressed not only in endothelial cells but also in monocytes/macrophages, sub-populations of bone marrow progenitors, and even some tumor cells [71], [72]. While abundant evidence supports the notion that most biological effects of VEGF-A

Tumor-associated fibroblasts

Tumor- or cancer-associated fibroblasts (TAFs or CAFs) are one of the major stromal elements implicated in tumor growth [23]. TAFs are enriched in PDGFR-α and are recruited to the tumors through gradient of PDGF-A and PDGF-C [108]. Previous studies showed that blocking only human VEGF-A in xenografted tumors is not sufficient to inhibit tumor growth since host VEGF-A, derived from various cell sources, including TAFs, compensates for the lack of tumor-derived VEGF-A [28], [109]. A marked TAF

Conclusion and perspectives

There is now clinical validation that therapies targeting the VEGF pathway are effective in slowing cancer progression and provide benefits to patients. However, tumors may be either intrinsically resistant or evolve to become resistant to such therapies. So far, no validated biomarkers predicting which patients are most likely to respond to the therapy have been identified. Preclinical studies indicate that refractoriness/resistance to anti-VEGF agents indeed may be due to multiple mechanisms.

Dr. Ferrara obtained his M.D. degree from the University of Catania Medical School in Italy in 1981. He joined Genentech Inc. in 1988 after doing his postdoctoral research at the University of California at San Francisco. At present, he is the Genentech Fellow in the Genentech Research Organization. Dr. Ferrara's main research interests are the biology of angiogenesis and the identification of its key regulators. His work on the isolation, molecular cloning and biological characterization of

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    Dr. Ferrara obtained his M.D. degree from the University of Catania Medical School in Italy in 1981. He joined Genentech Inc. in 1988 after doing his postdoctoral research at the University of California at San Francisco. At present, he is the Genentech Fellow in the Genentech Research Organization. Dr. Ferrara's main research interests are the biology of angiogenesis and the identification of its key regulators. His work on the isolation, molecular cloning and biological characterization of VEGF-A resulted in the development of bevacizumab, the first anti-angiogenic agent to be approved by the FDA for cancer therapy, and ranibizumab, which was FDA-approved for the treatment of neovascular age-related macular degeneration. Dr. Ferrara is author or co-author of over 260 publications and is the recipient of several scientific awards.

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