Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies
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
References (94)
- et al.
AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients
Cancer Cell
(2007) - et al.
Molecular and cellular biomarkers for angiogenesis in clinical oncology
Drug Discov. Today
(2007) - et al.
Hypoxic induction of an HIF-1alpha-dependent bFGF autocrine loop drives angiogenesis in human endothelial cells
Blood
(2006) - et al.
Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors
Cancer Cell
(2005) - et al.
PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment
Cancer Cell
(2009) - et al.
Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate
Exp. Cell Res.
(2007) - et al.
Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis
Cancer Cell
(2009) - et al.
Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche
Cancer Cell
(2009) - et al.
Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels
Cell
(2007) - et al.
Regulation of angiogenesis by hypoxia-inducible factor 1
Crit. Rev. Oncol. Hematol.
(2006)
Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1alpha-degradative pathway
J. Biol. Chem.
HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia
Cell Metab.
New developments in Hsp90 inhibitors as anticancer therapeutics: mechanisms, clinical perspective and more potential
Drug Resist. Updat.
Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF
J. Biol. Chem.
Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited
Cancer Cell
Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules
Cancer Cell
Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity
Cancer Cell
Antiangiogenic therapy elicits malignant progression of tumors to increase local invasion and distant metastasis
Cancer Cell
Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene
Cancer Cell
Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers
Drug Resist. Updat.
Role of the microenvironment in tumor growth and in refractoriness/resistance to anti-angiogenic therapies
Drug Resist. Updat.
CCI-779 inhibits rhabdomuosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/HIF1alpha/VEGF signaling
Neoplasia
Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases
Cancer Cell
Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis
Cancer Cell
Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer
Cancer Res.
Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal
J. Clin. Invest.
Modes of resistance to anti-angiogenic therapy
Nat. Rev. Cancer
Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors
J. Clin. Invest.
Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy
Clin. Cancer Res.
Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer
Cancer Res.
Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies
Cancer Res.
Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma
Cancer
Exploiting tumour hypoxia in cancer treatment
Nat. Rev. Cancer
Reversing hypoxic cell chemoresistance in vitro using genetic and small molecule approaches targeting hypoxia inducible factor-1
Mol. Pharmacol.
New therapeutic directions for advanced pancreatic cancer: targeting the epidermal growth factor and vascular endothelial growth factor pathways
Oncologist
Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1
Nat. Med.
Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study
J. Clin. Oncol.
Cell type-specific, topoisomerase II-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation by NSC 644221
Clin. Cancer Res.
Hypoxia-inducible factor-1 target genes as indicators of tumor vessel response to vascular endothelial growth factor inhibition
Cancer Res.
Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus
Cancer Res.
Pathways mediating resistance to vascular endothelial growth factor-targeted therapy
Clin. Cancer Res.
VEGF-targeted therapy: mechanisms of anti-tumour activity
Nat. Rev. Cancer
Lysyl oxidase is essential for hypoxia-induced metastasis
Nature
VEGF as a therapeutic target in cancer
Oncology
Angiogenesis: an organizing principle for drug discovery?
Nat. Rev. Drug Discov.
A role for VEGF as a negative regulator of pericyte function and vessel maturation
Nature
A RNA antagonist of hypoxia-inducible factor 1alpha, EZN-2968, inhibits tumor cell growth
Mol. Cancer Ther.
Cited by (117)
Targeting the oral tumor microenvironment by nanoparticles: A review of progresses
2024, Journal of Drug Delivery Science and TechnologyThe role of extracellular vesicles in the transfer of drug resistance competences to cancer cells
2022, Drug Resistance UpdatesCitation Excerpt :Moreover, some drugs may induce drug tolerance, by inducing an epithelial-mesenchymal transition (EMT) phenotype or cellular plasticity (Qin et al., 2020). The communication between cells present in the tumor microenvironment (TME) and cancer cells may also contribute to the selection and expansion of drug resistant clones (Correia and Bissell, 2012; Erin et al., 2020; Rapisarda and Melillo, 2009). Indeed, drug resistance in tumor cells may be mediated by intercellular communications with stromal cells present in the TME, such as cancer associated fibroblasts (CAFs) (Bu et al., 2020; Kadel et al., 2019) or immune cells such as tumor associated macrophages (TAMs) (Xavier et al., 2021).
Antiangiogenic therapy: Markers of response, “normalization” and resistance
2018, Critical Reviews in Oncology/HematologyCurrent progress in antivascular tumor therapy
2017, Drug Discovery TodayCitation Excerpt :However, the leaky tumor vessels and lymphatic impairment also elevate IFP to reduce the gradient of drug penetration. Because tumor cells are often located more than 100 μm from nearby vessels, tumor hypoxia and treatment resistance are induced by the limited distance of oxygen perfusion and drug penetration [34]. Primeau et al. showed that the distances of doxorubicin penetration and hypoxic regions from the nearest vessels were ∼40–50 μm and ∼90–140 μm, respectively, in mammary sarcoma EMT6, prostatic-PC3 and mammary adenocarcinoma 16C tumors [35].