Modulation of cell death in the tumor microenvironment*

https://doi.org/10.1053/srao.2003.50004Get rights and content

Abstract

The microenvironment of solid human tumors is characterized by heterogeneity in oxygenation. Hypoxia arises early in the process of tumor development because rapidly proliferating tumor cells outgrow the capacity of the host vasculature. Formation of solid tumors thus requires coordination of angiogenesis with continued tumor cell proliferation. However, despite such neovascularization, hypoxia is persistent and frequently found in tumors at the time of diagnosis. Tumors with low oxygenation have a poor prognosis, and strong evidence suggests this is because of the effects of hypoxia on malignant progression, angiogenesis, metastasis, and therapy resistance. The presence of viable hypoxic cells is likely a reflection of the development of hypoxia tolerance resulting from modulation of cell death in the microenvironment. This acquired feature has been explained on the basis of clonal selection—the hypoxic microenvironment selects cells capable of surviving in the absence of normal oxygen availability. However, the persistence and frequency of hypoxia in solid tumors raises a second potential explanation. We suggest that stable microregions of hypoxia may play a positive role in tumor growth. Although hypoxia inhibits cell proliferation and in tumor cells will eventually induce cell death, hypoxia also provides angiogenic and metastatic signals. The development of hypoxia tolerance will thus allow prolonged survival in the absence of oxygen and generation of a persistent angiogenic signal. We will discuss the concept of hypoxia tolerance and review mechanisms used by cancer cells to acquire this phenotype. The concept of hypoxia tolerance has important implications for current and future therapeutic approaches. Most therapeutic efforts to combat hypoxia have focused on targeting the presence of hypoxia itself. Our hypothesis predicts that targeting the biological responses to hypoxia and the pathways leading to hypoxia tolerance may also be attractive therapeutic strategies. Copyright 2003, Elsevier Science (USA). All rights reserved.

Section snippets

The concept of hypoxia tolerance

Evidence implicating hypoxia in the pathogenesis of solid human tumors continues to accumulate. Tumor hypoxia was hypothesized approximately 50 years ago to be important in the radiotherapeutic management of cancer because hypoxic cells are intrinsically more resistant to radiation than aerobic cells.1 This initial interest in the radiobiological consequences of tumor hypoxia formed the basis of decades of research that, in recent years, has led to a close examination of the biological

Mechanisms of hypoxia tolerance

The formation and continued proliferation of solid tumors requires persistent angiogenesis. Reminiscent of many biological processes, angiogenesis is the result of subtle and often complex interactions balancing pro- and antiangiogenic molecules. This equilibrium is upset in various diseases, including cancer. Angiogenesis is virtually nonexistent in healthy adult tissue with the exception of a few physiological processes such as wound healing and the female menstrual cycle.21, 22 Stable

Therapy implications

The fact that hypoxia negatively impacts on therapy is well established. Hypoxic cells are radiation and chemoresistant for a variety of reasons,51 and thus effective therapy requires strategies to overcome this resistance. Many attempts have been made, most of these focused on trying to restore normal oxygenation (or mimic it) to the tumor. The concept that tumor cells become hypoxic tolerant, and furthermore that the presence of microregions of hypoxia may be advantageous to overall tumor

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    *

    Address reprint requests to Bradly G. Wouters, PhD, Department of Experimental Radiation Oncology, UNS 50/Box 23, azM/University of Maastricht, Postbox 616, 6200 MD Maastricht, The Netherlands.

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