Evading tumor evasion: Current concepts and perspectives of anti-angiogenic cancer therapy
Introduction
It was proposed that tumor growth and metastasis are angiogenesis-dependent, and inhibition of tumor neovascularization (e.g., by an antibody to tumor angiogenic factor (TAF)) might provide a novel strategy for cancer therapy (Folkman, 1971). The first part of this hypothesis is now thoroughly accepted, and tumor angiogenesis is considered a hallmark of cancer development and progression (Hanahan and Weinberg, 2000). Nevertheless, from its early days, the field was confronted with some skepticism regarding the therapeutic potential of the anti-angiogenic strategy. It was argued that this approach might be less effective or simply not effective in the treatment of established tumors and/or late-stage cancer. Additionally, inhibition of vascular supply might:
- (i)
elevate tumor hypoxia, leading to evolution of hypoxia-insensitive tumors with enhanced local invasiveness and distant metastasis activity;
- (ii)
decrease the efficacy of oxygen sensitive radiotherapy;
- (iii)
reduce the tumor delivery, and thereby the efficacy, of chemotherapy.
In contrast, an extensive body of experimental data was generated that demonstrates the efficacy of anti-angiogenic therapy to potently inhibit local tumor growth and metastasis (Abdollahi et al., 2005b, Folkman, 2007, Kerbel and Folkman, 2002, Broxterman and Georgopapadakou, 2007). Moreover, synergistic activity of anti-angiogenic agents was reported in dual and trimodal combinations with chemotherapy and/or radiotherapy (Huber et al., 2005, Jain, 2008, Duda et al., 2007). We learned that the tumor endothelium might also be a critical target of conventional cancer therapies (Folkman and Camphausen, 2001). Novel insights into the intricate intercellular communication between tumors and tumor microenvironments and the multifaceted nature of pro-angiogenic and anti-angiogenic signals in the modulation of endothelial cell survival, vascular permeability, inflammation and other key processes in tumor pathophysiology have all improved our understanding of the anti-tumor effects of anti-angiogenic therapies (Ellis and Hicklin, 2008, Abdollahi et al., 2005b). However, the most striking empirical evidence was provided by the encouraging clinical performance of anti-angiogenic therapy in combination with conventional cancer therapies (e.g., chemotherapy) in late-stage, heavily pretreated metastatic cancer patients (Duda et al., 2007, Folkman, 2007, Ellis and Hicklin, 2008, Jain, 2008). These data are intriguing because various combinations of diverse chemotherapeutic agents often failed to add any significant therapeutic benefit in these patients. Later clinical studies demonstrated superior efficacy of stand-alone therapy with multi-targeted angiogenesis inhibitors over standard therapy in metastatic diseases, such as in metastatic renal cell carcinoma (Motzer et al., 2009, Motzer et al., 2007). Therefore, anti-angiogenic therapy is now unequivocally considered the fourth modality of cancer treatment in addition to surgery, chemo- and radiotherapy.
Section snippets
Targeting the tumor endothelium vs. tumor cells
Human cancer is considered a genetic disease caused by the sequential accumulation of mutations in normal cells. The classical tumor cell genome-centric cancer research community is expending tremendous effort in identifying critical tumor-deriving mutations, with the long-term goal of developing therapeutic strategies against the altered function of these genes (Kaiser, 2008, TCGA, 2008). According to the most recent report of The Cancer Genome Atlas network (TCGA, http://cancergenome.nih.gov
Lack of acquired drug resistance in endothelial cells
Acquired drug resistance is a major obstacle of tumor cell targeting therapies (Broxterman et al., 2009). Compared to genetically unstable tumor cells, the endothelial cells recruited by tumors to form the tumor vasculature are proposed to be genetically more stable and therefore less susceptible to the development of acquired drug resistance (Kerbel, 1991, Folkman et al., 2000, Abdollahi et al., 2005b). For example, single amino acid mutations in the kinase domain of the BCR-ABL oncogene
Radiotherapy
Radiotherapy is an integral component of cancer therapy. Approximately two thirds of all cancer patients receive radiotherapy during the course of their disease. However, the precise molecular mechanism of radiation-induced anti-tumor effects is still not completely understood. The conventional explanation for the effectiveness of radiotherapy is that tumor cells are the principal target, and therapy-induced DNA damage causes them to undergo mitotic or programmed cell death (Bedford and Dewey,
The redundancy in angiogenic signals: therapeutic implications
It was proposed that anti-angiogenic agents could be divided into two categories, direct and indirect angiogenesis inhibitors (Abdollahi et al., 2003c). This classification is based on the consideration that endothelial cells are the principal targets of anti-angiogenic therapy. Therefore, inhibition of pro-angiogenic signals induced by the tumor or tumor-stroma is considered an indirect mechanism. In contrast, direct inhibitors are proposed to exert their effects on angiogenic endothelium
Potential tumor evasive mechanisms
The proposition that most of the current anti-angiogenic approaches exert their effects via inhibition of angiogenic signals induced by the tumor cells implies that the same evolutionary forces that drive tumor cell fitness and natural selection may also apply to tumor evasion from indirect anti-angiogenic treatment. However, the constraints defined by the ability of tumor cells to express, from a limited set of endogenous pro-angiogenic factors, the angiogenic “bottleneck” constitutes a
Evading tumor evasion
What are the therapeutic implications of the proposed tumor evasive mechanisms against anti-angiogenic therapy? To rationally design anti-angiogenic therapies, we need to detect the angiogenic profiles of tumors prior to therapy. Further, development of successful anti-angiogenic combinations requires the prediction of tumor responses to single-, dual- or multi-targeted angiogenesis inhibitors. We anticipate differences in the predictability of therapy responses based on the underlying evasive
Local tumor invasion and distant metastasis as evasive mechanisms
An extensive body of experimental data shows that anti-angiogenic therapy potently inhibits local tumor growth and impairs the development and progression of tumor metastasis. Nevertheless, local invasion and distant metastasis have been intensely debated as potential adverse effects of anti-angiogenic therapy (Browder et al., 2002, Blagosklonny, 2001, Blagosklonny, 2004, Steeg, 2003, Kieran et al., 2003). The argument is based on the hypothesis that anti-angiogenic therapy might select for
Endogenous angiogenesis inhibitors
In contrast to indirect angiogenesis inhibitors that neutralize the effect of pro-angiogenic factors, endogenous angiogenesis inhibitors such as endostatin and angiostatin are proposed to exert “direct” anti-angiogenic effects in the tumor endothelium (Nyberg et al., 2005, Abdollahi et al., 2003c). For example, this is supported by the ability of endostatin to inhibit angiogenesis induced by several different pro-angiogenic proteins (Abdollahi et al., 2004). However, compared to pharmacological
Conclusion
The field of anti-angiogenic therapy has evolved very rapidly. However, the prevailing anti-angiogenic strategy is to neutralize the effect of only one or a few pro-angiogenic factors. The redundancy of pro-angiogenic signals secreted by tumor cells or indirectly via tumor stroma might limit the therapeutic efficacy of drugs that block the effects of a single pro-angiogenic protein. Thus, systemic characterization of a tumor's angiogenic profile and identification of a tumor's fitness landscape
Acknowledgments
This article is dedicated to the memory of the greatest mentor and friend, Dr. Judah Folkman, who passed away while preparing the manuscript. This work was supported in part by the Nasa Specialized Center of Research NNJ04HJ12G, German Krebshilfe (Deutsche Krebshilfe, Max-Eder 108876), DFG National Priority Research Program: the Tumor–Vessel Interface “SPP1190”, and the German Federal Ministry of Research and Technology (Bundesministerium für Bildung und Forschung–BMBF 03NUK004A/C).
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