Review
Tumor and stromal pathways mediating refractoriness/resistance to anti-angiogenic therapies

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Identification and characterization of VEGF as an important regulator of angiogenesis, and FDA approval of the first anti-angiogenic drugs, 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 recurrence. Recent studies in several experimental models suggest that tumor and non-tumor (stromal) cell types may be 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

It is generally accepted that angiogenesis (Box 1) is a rate-limiting process in tumor growth 1, 2, 3. Over the last few years, several clinical trials have demonstrated the clinical benefits conferred by anti-angiogenic agents on cancer and age-related macular degeneration (reviewed in 2, 4).

Vascular endothelial growth factor (VEGF) and its receptors represent the most commonly targeted signaling pathway in angiogenesis [5]. VEGF-A (VEGF hereafter) is the prototype member of a gene family that also includes VEGF-B, VEGF-C, VEGF-D and placental growth factor (PlGF). VEGF binds to two tyrosine kinase receptors: VEGFR1 and VEGFR2. Despite its weaker binding affinity to VEGF compared with that of VEGFR1, it is VEGFR2 that primarily mediates VEGF signaling within endothelial cells [6]. The current FDA-approved anti-angiogenic agents inhibit the VEGF pathways. The first anti-angiogenic agent to be approved is bevacizumab (Avastin, Genentech), a humanized anti-VEGF monoclonal antibody. Administration of bevacizumab, in combination with cytotoxic chemotherapy, conferred benefits to patients with metastatic colorectal cancer, non-squamous, non-small-cell lung carcinoma and metastatic breast cancer 7, 8, 9. Most recently, bevacizumab has been FDA-approved also for the therapy of renal cell carcinoma (in combination with interferon-alfa) and glioblastoma multiforme. Additionally, two small-molecule inhibitors targeting VEGFRs and other kinases, sorafenib (Bayer and Onyx pharmaceuticals) and sunitinib (Pfizer), have been approved based on their efficacy in treating renal or hepatocellular cancer 10, 11, 12, 13. However, not all cancer patients benefit from such anti-angiogenic therapies, and some who benefit initially might develop resistance during the treatment as well as showing some adverse effects 11, 13, 14. Hence, there is an urgent need to understand the mechanisms (intrinsic or acquired) that mediate refractoriness/resistance to anti-angiogenic agents.

This article will discuss current understanding of tumor- and stromal-derived molecular pathways mediating VEGF-independent tumor angiogenesis. Significant overlaps occur in several cases.

Section snippets

Vascular co-option and acquisition of an invasive phenotype as potential mechanisms of resistance to anti-angiogenic therapy

Several mechanisms of inherent refractoriness or acquired resistance to antiangiogenic agents have been identified in preclinical models (reviewed in 11, 15). Tumor cells may become less sensitive to hypoxia or nutrient deprivation induced by anti-angiogenic agents via selection of resistant clones [16]. Tumor vessels can also be or become less sensitive to anti-angiogenic agents, and sustained tumor angiogenesis could occur through VEGF-independent mechanisms 11, 13, 15, 17. Also, in some

Members of the VEGF pathway

Various members of the VEGF pathway have been implicated in incomplete response to VEGF-A blockers (see Table 1). PlGF is a member of VEGF family that binds specifically to VEGFR1 41, 42. Upregulation of VEGF and PlGF has been reported in patients treated with anti-angiogenic agents targeting the VEGF pathway 43, 44. This observation suggested the possibility that PlGF may participate in tumor evasion to some antiangiogenic therapies. It has recently reported that PlGF inhibition with a

Contribution of stromal cells to tumor angiogenesis and tumor resistance to anti-VEGF therapies

There is now much evidence that tumor-infiltrating cells play a key part in tumorigenesis and angiogenesis 66, 67. Cross-talk between tumor cells and various types of stromal cell, mediated by cytokines and chemokines, regulates tumor growth [68]. The importance of stromal cells in tumorigenesis was highlighted in a recent study indicating that stromal gene expression signatures can be an independent predictor of outcome in breast cancer [69]. Stromal cells comprise fibroblasts, various

Concluding remarks

There is clinical validation that therapies targeting the VEGF pathway are effective in slowing cancer progression and that they can provide benefits to patients. However, tumors may be intrinsically resistant or evolve to become resistant to such therapies. Preclinical studies indicate that resistance to anti-VEGF agents may be due to multiple mechanisms.

Several well-defined signaling pathways (e.g. FGF, Dll4, PlGF/VEGFR1, and VEGF-C/VEGFR2) have been implicated, and clinical trials are

Glossary

RIP-Tag
Transgenic mouse strain that develops insulinoma (tumor of the endocrine pancreas). Tumorigenesis is driven by the SV40 large T-antigen under control of the insulin promoter.
FOLFOX
Chemotherapy regimen used for treatment of colorectal cancer. It comprises folinic acid (FOL), 5-fluorouracil (F) and oxaliplatin (OX). Depending on dosing and scheduling, several variants of the FOLFOX regimen are currently used.
CT26
An N-nitroso-N-methylurethane-(NNMU)-induced, undifferentiated colon carcinoma

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