Angiogenesis inhibitors increase tumor stem cells

Abstract

The clinical efficacy of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway has recently been met with numerous phase III failures that showed modest survival benefits. Understanding the resistance mechanisms of antiangiogenic therapy is essential to overcoming the limited effectiveness of VEGF-pathway inhibitors.

A recent study published in the Proceedings of the National Academy of Sciences provides a novel explanation to the treatment limitations of angiogenesis inhibitors and suggests a potential strategy to improve the clinical utility of these agents.

Keywords: :

• angiogenesis
• cancer stem cells
• tumor hypoxia

Angiogenesis Inhibitors Increase Tumor Stem Cells

Since 1971, the angiogenic pathway has been a valid target for anticancer drug development. Dr. Folkman theorized that a tumor was dependent on the recruitment of blood vessels in order to grow and by blocking this process one could inhibit the progression.¹ This basic idea led to the investigation of hundreds of potential angiogenesis inhibitors, with bevacizumab [vascular endothelial growth factor (VEGF) neutralizing antibody] being the first agent to gain FDA approval. This was followed by the approval of several VEGF receptor tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib and axitinib) that targeted different parts of the angiogenic pathway. Nonetheless, clinical experience with bevacizumab has proven to be rather perplexing for most oncologists (improvement in progression free survival, but little to no benefit in overall survival). In fact, of the 16 pivotal phase III trials conducted with bevacizumab in solid tumors only three were positive for overall survival (first-line mCRC,² second-line mCRC³ and first-line recurrent/advanced NSCLC⁴). In 2011, this concern made headlines when FDA rescinded the approval of bevacizumab for the treatment of breast cancer following the failure of two phase III clinical trials to demonstrate an improvement in overall survival for first-line breast carcinoma.^5,6

Emerging clinical and preclinical evidence suggested that the limited efficacy observed with angiogenesis inhibitors arise from tumors eliciting evasive resistance to these regimens. Interestingly, recent studies in preclinical models have demonstrated an increase in tumor invasiveness and metastasis in response to VEGF-targeted therapies or VEGF gene inactivation.^7–9 Angiogenesis inhibitors often cause tumor vessels to regress resulting in vessel normalization. This vascular pruning can also cause intratumoral hypoxia, which in turn activates the hypoxia-inducible 1 factor α (HIF-1α) and HIF-mediated pathways to promote invasion and metastasis from the tumor.¹⁰ Moreover, several reports have implicated a critical role for hypoxia and HIF in cancer stem cell (CSC) proliferation, self-renewal, and maintanence.¹¹ The tumor-initiating properties and metastatic potential of CSCs make them key drivers of tumor growth and therapy resistance.

In the recent study published in the Proceedings of the National Academy of Sciences, Conley and colleagues hypothesized that hypoxia induced by the administration of angiogenesis inhibitors might accelerate tumor growth and metastasis by increasing the CSC population.¹² Using breast cancer xenograft models and the Aldefluor assay to identify the CSC population, they showed that by generating intratumoral hypoxia with sunitinib malate and bevacizumab, this resulted in an increase in the population of cancer stem cells. Concentrated populations of CSCs were predominantly localized in hypoxic regions within tumors from drug-treated mice. Human breast cancer cell lines grown in vitro under mild hypoxic conditions also resulted in an expansion of the CSC population. Furthermore, it was shown that HIF-1α was primarily responsible for the stem cell enrichment and that the hypoxia-induced increase in the CSC population was mediated through activation of the AKT/β-catenin regulatory pathway.

Taken together, these findings suggest that antiangiogenic therapy leads to the generation of tumor hypoxia and results in an increase in the CSC population. This CSC niche may be responsible for mediating tumor metastasis and resistance to cancer treatments. These studies may help explain the limited clinical utility of angiogenesis inhibitors and add another dimension to the existing modes of resistance to angiogenesis inhibitors that already involve complex tumor and host-mediated pathways.^13,14 Understanding the mechanisms of resistance is essential for developing strategies that will allow for optimal exploitation of the potential of angiogenesis inhibitors. Data from the current study have tremendous clinical implications and reveal a new approach to overcome resistance to antiangiogenic agents by targeting the cancer stem cell population. Clinically, angiogenesis agents have a role, albeit often transient, and patients relapse with more invasive metastatic disease resulting in minimal overall survival advantage. If we could identify a cancer stem cell-targeting agent and combine it with an angiogenesis inhibitor, we might develop a synergistic combination that represents an improved therapeutic regimen with better clinical efficacy.

Acknowledgments

This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.