Angiogenesis and the tumor space–time continuum

Abstract

Tumors invade space through cancer cell proliferation and tumor mass expansion. Tumor growth is maintained over time using the cancer stem cell pool, which is the cell population with self-renewal potential. The work by Conley et al. (1) provided evidence that antiangiogenic agents increase cancer stem cells through the generation of tumor hypoxia. These findings are in accordance with the findings showing that hypoxia induces stem cell markers expression in cancer cells (2, 3) and that antiangiogenic therapy elicits malignant progression of tumors (4). Thus, there is now sufficient evidence to reconsider the role of tumor angiogenesis in cancer progression. Tissues need nutrients and oxygen for growth, and tumors behave as other tissues. This view is the classical view, in which, according to the work by Folkman (5), the role of tumor angiogenesis fulfills the function of normal vessels that is to deliver oxygen and metabolites and remove waste products. However, tumor vessels are abnormal and fail to fulfill these functions. Therefore, tumors have naturally chronic and cyclic hypoxic regions. This paradoxical consequence of tumor angiogenesis is that, because of its deficiencies, it also generates hypoxia. In pathology such as cancer, a defect in a physiological process does not necessarily suppress the function of the process but can generate a novel function required for disease development. Here, the other function of tumor angiogenesis is to maintain tumor growth over time through cancer stem cell increase. This dual nature of tumor angiogenesis ensures a balance between growth over space (by providing oxygen and nutrients; i.e., physiological function) and growth over time (by generating hypoxic regions that increase the cancer stem cell pool; i.e., pathophysiological function). Hence, tumors require both the physiological and pathophysiological functions of tumor angiogenesis. Therefore, the significance of tumor angiogenesis is the generation of a tumor space–time continuum.