Modulation of the tumor vasculature and oxygenation to improve therapy

Abstract

The tumor microenvironment is increasingly recognized as a major factor influencing the success of therapeutic treatments and has become a key focus for cancer research. The progressive growth of a tumor results in an inability of normal tissue blood vessels to oxygenate and provide sufficient nutritional support to tumor cells. As a consequence the expanding neoplastic cell population initiates its own vascular network which is both structurally and functionally abnormal. This aberrant vasculature impacts all aspects of the tumor microenvironment including the cells, extracellular matrix, and extracellular molecules which together are essential for the initiation, progression and spread of tumor cells. The physical conditions that arise are imposing and manifold, and include elevated interstitial pressure, localized extracellular acidity, and regions of oxygen and nutrient deprivation. No less important are the functional consequences experienced by the tumor cells residing in such environments: adaptation to hypoxia, cell quiescence, modulation of transporters and critical signaling molecules, immune escape, and enhanced metastatic potential. Together these factors lead to therapeutic barriers that create a significant hindrance to the control of cancers by conventional anticancer therapies. However, the aberrant nature of the tumor microenvironments also offers unique therapeutic opportunities. Particularly interventions that seek to improve tumor physiology and alleviate tumor hypoxia will selectively impair the neoplastic cell populations residing in these environments. Ultimately, by combining such therapeutic strategies with conventional anticancer treatments it may be possible to bring cancer growth, invasion, and metastasis to a halt.

Introduction

In the development of a cancer, the transformation into a neoplastic and progressively invasive tumor occurs though a multitude of etiologies. Oncogenic lesions, coupled with inhibition of tumor suppressors, together contribute to cellular transformation. Genomic, proteomic, post-translational, and epigenetic mutations are responsible for activating oncogenes and inhibiting tumor suppressor genes. Several essential characteristics are present in malignancies; a key element of malignant transformation being the loss of regulatory control mechanisms. Cancer cells not only possess heightened rates of cell proliferation and aberrant cell cycle checkpoints, but also lose contact-inhibited growth regulation.

The developing tumor contains a distinct cellular compartment that retains stem-like cell characteristics, namely multipotency, self-renewal and proliferation potential, and this in turn drives oncogenesis and tumor progression. Thus a discrete subset of cells within a tumor possesses the capability of self-renewal and multipotency that gives rise to a heterogeneous population of cancer cells. Although cancer stem cells can vary by definition, they generally comprise less than 10% of the population of a tumor. Still, cancer stem cells have been implicated as a key component in the formation and spread of human cancers to distant sites.

In addition to the variety of neoplastic cells, many other cell types are present in the tumor milieu. Examples include fibroblasts, endothelial cells, hematopoietic-derived cells, and immune cells, which normally monitor this environment for foreign bodies. In cancer, particularly at the later stages of transformation and invasion, normal immune functions are subverted, leading to recognition of the tumor as part of the host, rather than as an invading foreign entity.

This cellular heterogeneity coupled with key physical and structural tissue components which form the extracellular matrix define the tumor microenvironment. The matrix is deposited as a mix of such proteins as collagens, fibronectin, laminins, hyaluronan, plasminogens, proteases, and numerous others which collectively form an inflexible scaffold to which cells attach. In addition, other secreted cellular proteins such as cytokines and extracellular matrix remodeling proteins normally reside in the extracellular matrix and contribute to its turnover regulation.

The tumor microenvironment is not static, but rather highly variable depending on tumor type and stage of cancer development. A critical factor impacting variations in the tumor microenvironment is the tumor supportive blood vessel network. The abnormal tumor vasculature and its physiologic consequences serve as an over-arching modulator of the tumor microenvironment affecting the composition and interaction of its constituents to impact tumor progression, cell dissemination, response to anticancer therapeutics, and cancer patient outcomes.

The deleterious effects of the tumor microenvironment on cancer therapy outcomes were first recognized in the 1950s when the possible negative consequences of tumor hypoxia for radiotherapy efficacy were postulated. Unfortunately, this issue has not been resolved. Indeed it has become abundantly clear that the effect of the tumor microenvironment is far more insidious than initially anticipated; now known to impact all conventional anticancer therapies, fundamental cancer cell biology, gene expression, and metastatic incidence. This review provides a historical context to our current perspectives of interventions strategies seeking to overcome the negative therapeutic consequences of the aberrant tumor microenvironment.