Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies

https://doi.org/10.1016/j.drup.2009.03.002Get rights and content

Abstract

Angiogenesis, a key process for the growth of human cancers, has recently been exploited for the development of a novel class of cancer therapeutics that was thought to have wide applications and not to induce resistance in the clinical setting. Indeed, anti-angiogenic therapy has become an important option for the management of several human malignancies. However, a significant number of patients either do not respond to anti-angiogenic agents or fairly rapidly develop resistance. In addition, the benefit of anti-angiogenic therapy is relatively short-lived and the majority of patients eventually relapses and progresses. Several mechanisms of resistance to anti-angiogenic therapy have been recently proposed. The current review focuses on the role of intra-tumor hypoxia as a mechanism of resistance to anti-angiogenic agents and speculates on therapeutic approaches that might circumvent resistance and thereby improve clinical outcome.

Introduction

Studies over the past 30 years have shown that angiogenesis is an important process contributing to the progression of cancer from an in situ lesion to invasive and metastatic disease, providing the rationale for the development of anti-angiogenic therapies (Kerbel and Folkman, 2002, Folkman, 2007). To this date, several anti-angiogenic approaches have been investigated in animal models as well as in the clinic. Targeting the vascular endothelial growth factor (VEGF)/VEGF receptor pathway, alone or in combination with chemotherapy, has shown clinical benefit in patients with metastatic colorectal cancer, advanced non-small cell lung cancer, renal cell carcinoma, hepatocelluar carcinoma and metastatic breast cancer (Ferrara, 2005, Shojaei and Ferrara, 2007a, Ellis and Hicklin, 2008b). Anti-angiogenic agents are then an integral component of current therapeutic approaches of combination chemotherapy and/or molecularly targeted therapies.

Although anti-angiogenic therapy is becoming an important option for the treatment of cancer, its systematic application remains problematic because of both poor understanding of its mechanisms of action and occurrence of resistance (Jain et al., 2006). Indeed, a significant fraction of patients does not respond to anti-angiogenic therapy (Burris and Rocha-Lima, 2008), whereas those who respond have a relatively modest survival benefit. In addition, despite disease stabilization and an increase in the proportion of progression free patients, tumors eventually become resistant to anti-angiogenic agents and relapse (Bergers and Hanahan, 2008, Ellis and Hicklin, 2008a, Kerbel, 2008, Shojaei and Ferrara, 2008b). In the end, which patients may potentially benefit from the addition of an anti-angiogenic agent to the therapeutic regimen remains poorly understood.

Multiple mechanisms may account for the activity of anti-VEGF agents in cancer patients including, but not limited to, their effect on tumor vasculature (Ellis and Hicklin, 2008b). Evidence has been provided supporting both a vascular regression, which is presumably associated with increased intra-tumor hypoxia (Kerbel and Folkman, 2002) and a so-called “normalization” of tumor vasculature, with a consequent decrease in interstitial pressure and better delivery of chemotherapy (Jain, 2005). These conflicting and still largely controversial observations emphasize how important it is to better understand the effects of anti-angiogenic agents on the tumor microenvironment to eventually further characterize the mechanisms that mediate resistance.

Hypoxia, areas of low oxygen levels, is a hallmark of solid tumors due to an imbalance between oxygen delivery and consumption (Brown and Wilson, 2004). The presence of hypoxia in solid tumors is associated with resistance to radiation therapy and chemotherapy, selection of more invasive and metastatic clones and poor patient prognosis (Harris, 2002, Hockel and Vaupel, 2001). Hypoxia inducible factor-1 (HIF-1) is a master regulator of cellular adaptation to oxygen deprivation and may act as a survival factor of hypoxic cancer cells, primarily by activating transcription of genes involved in angiogenesis, glycolytic metabolism, oxygen consumption, migration and invasion (Semenza, 2007). HIF-1 is a heterodimeric protein consisting of a constitutively expressed HIF-β subunit and a HIF-α subunit, the expression of which is regulated by the cellular O2 concentration (Wang et al., 1995). Under normoxic conditions, HIF-1α is continuously hydroxylated by oxygen-dependent prolyl hydroxylases, and targeted for ubiquitination and proteasomal degradation (Pouyssegur et al., 2006). On the contrary, under hypoxic conditions the HIF-α subunit is stabilized and translocates to the nucleus where it dimerizes with HIF-1β (also known as aryl hydrocarbon receptor nuclear translocator, ARNT) and, by binding to hypoxia responsive elements (HRE), activates transcription. Expression of HIF-1α has been demonstrated in many human cancers and is associated with poor prognosis and treatment failure (Koukourakis et al., 2006, Aebersold et al., 2001, Birner et al., 2000, Birner et al., 2001, Bos et al., 2003).

In this review we will discuss the main mechanisms that have been implicated in resistance to anti-angiogenic agents with particular emphasis on the role that intra-tumor hypoxia and activation of HIF-1 dependent responses might play. Our conclusions may contribute not only to a better appreciation of the role of the tumor microenvironment in mediating resistance to anti-angiogenic agents but also to the design of novel therapeutic approaches.

Section snippets

Mechanisms of resistance to anti-angiogenic therapy

Resistance to anti-angiogenic agents is a complex phenomenon that can be broadly classified as intrinsic and acquired resistance.

The hypoxic tumor microenvironment and response to anti-angiogenic agents

The fine balance between oxygen and nutrients supply by blood vessels and proliferation of cancer cells determines the onset of intra-tumor hypoxia and the induction of the angiogenic switch. Tumors that fail to activate angiogenic pathways may remain dormant and do not progress. The key regulator of hypoxia-induced angiogenesis is the transcription factor hypoxia inducible factor (HIF)-1. Multiple HIF-1 target genes are involved in different steps of angiogenesis: induction of growth factors

Targeting the hypoxic tumor microenvironment to overcome resistance to anti-angiogenic therapy

Based on the evidence discussed so far, it is conceivable that the increase in intra-tumor hypoxia induced by anti-angiogenic agents may be part of a fundamental mechanism by which cancer cells adapt to the decreased blood supply and escape from its potential detrimental effects. The biological consequences of intra-tumor hypoxia and its potential role for the development of tumor-specific therapeutics have been subject of investigation for many years. However, only over the last two decades

Conclusion and perspectives

The excitement for novel therapeutic strategies approaching the clinical arena is invariably tempered by the complexity of translating findings from preclinical models to cancer patients. Clinical trials with anti-angiogenic agents have initially generated great enthusiasm for the potential universal application of this therapeutic approach to human cancers. However, the premise that the efficacy of anti-angiogenic agents would not be limited by the inevitable occurrence of drug resistance has

Acknowledgments

The authors would like to thank members of the Tumor Hypoxia Laboratory and Dr. R.H. Shoemaker for helpful discussion. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply

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