Tumor angiogenesis has been a subject of wide interest over the past decade, following from the groundbreaking work of Folkman and colleagues. Uncontrolled angiogenesis is present in almost every tumor type and leads to immature, malformed vessels lined by endothelial cells with aberrant morphology, loosely attached pericytes, and an abnormal basal membrane. These vessels are characterized by their chaotic organization and increased permeability causing elevated interstitial fluid pressure. Vascular malformations do not provide an efficient supply of oxygen, nutrients, or therapeutic drugs to tumor tissue. This leads to significant treatment resistance.[3,4]
In this issue of ONCOLOGY, Sato et al provide a comprehensive overview of different strategies for antiangiogenic and antivascular targeted therapies, focusing on those currently in clinical trials. This commentary will focus on the need for methods to monitor changes in the microenvironment and angiogenic responses to vascular-targeted therapies, alone and in combination with cytotoxic therapies.
Considerations When Using Antiangiogenic Agents
Antiangiogenesis was first considered as a treatment option based on the hope that it would destroy tumor vasculature to the point that tumors regressed as a result of severe oxygen starvation. While this approach seems theoretically attractive, that outcome has not proven to be the case for antiangiogenic therapies.
In fact, correcting the overexpression of proangiogenic factors (such as vascular endothelial growth factor [VEGF]) by antiangiogenic compounds leads to a better balance of pro- vs antiangiogenic factors. This can lead to maturation and/or pruning of immature vessels, causing "normalization" of tumor vasculature.[5-10] Of utmost importance in "normalization" is whether oxygen and drug delivery are enhanced, and if so, the kinetics of the responses.
The concept of "vascular normalization" has been evaluated at the preclinical level in numerous studies, briefly summarized below. A murine mammary carcinoma (McaIV) and a human colon carcinoma cell line (LS174T) showed less tortuous vessels 3 days after blocking VEGF receptor (VEGFR)2 with the murine VEGF antibody DC101. Remaining vessels were more uniformly covered by pericytes and basement membrane. These normalized vessels were less leaky, as reflected by a reduction of intratumoral fluid pressure, and there was improvement in oxygenation, as assessed by hypoxia marker drug uptake. Vessel normalization was followed by vessel regression at day 5, however, demonstrating the transient nature of this response. In a neuroblastoma (NB-1691) xenograft model, VEGF inhibiton by bevacizumab (Avastin) led to better intratumoral drug delivery and efficacy. Both bevacizumab and DC101 improved tumor tissue oxygenation[9,11] in human glioma xenografts, resulting in increased efficacy of radiation treatment.
Small-molecule inhibitors of VEGF receptor activity have also shown promise. After 4 days of treatment of a non–small-cell lung cancer (NSCLC) xenograft tumor line with imatinib (Gleevec), a platelet-derived growth factor receptor (PDGFR) inhibitor, investigators observed a significant reduction of VEGF expression and vascular normalization (defined by tight pericyte-endothelial cell coverage). In addition, they noted improved oxygenation after 1 to 2 weeks of therapy and an enhanced antitumor effect when imatinib was combined with docetaxel.[13,14]
Not all reports have been positive with respect to whether normalization occurs after initiation of VEGF inhibition, however. Fenton et al reported variable results in different tumor lines and suggested that direct sensitization of tumor endothelial cells to radiation therapy following withdrawal of VEGF signaling might be more important in explaining radiosensitization than any change in oxygenation. The mechanism of treatment failure of individual tumors is not fully understood. One possible explanation is the ability of certain tumor cells to dedifferentiate and build vessel-like-structures—the so-called vasculogenic mimicry. This process of cell plasticity occurs mainly in highly aggressive tumors and was first discovered in highly metastatic melanoma. These vessels seem not to respond to antiangiogenic treatment.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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