Associate editor: B. TeicherModulation of the tumor vasculature and oxygenation to improve therapy
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.
Section snippets
Aberrant vascular networks
Survival of tumor cells and subsequent tumor development require an adequate supply of oxygen and nutrients. These are initially supplied from the host vascular system, but the demand for these critical factors soon exceeds the supply from this source, thus tumors develop their own functional vascular supply (Folkman, 1986) from the normal host vascular network by the process of angiogenesis (Bergers & Benjamin, 2003). Despite the importance of this neo-vasculature, the system that actually
Cancer stem cells and metastases
Cancer stem cells, also known as tumor initiating cells (TICs), represent a subpopulation of tumor cells that selectively possess tumor initiation and self-renewal capacity and the ability to give rise to bulk populations of non-tumorigenic cancer cell progeny through differentiation (Jordan et al., 2006, Gupta et al., 2009). TICs were initially described in leukemias (Lapidot et al., 1994) but subsequently have been identified in a variety of solid cancers (Jordan et al., 2006, Gupta et al.,
The tumor microenvironment as a double edged sword
A dramatic shift in research emphasis arose as a consequence of the recognition that the pathophysiological characteristics which distinguish tumors from normal tissues, aid their progression and dissemination, and make them refractory to conventional anticancer therapies (Fig. 6), might be exploitable. Indeed entire new areas of research and approaches to cancer therapy have emerged that seek to take advantage of these features of tumors to turn them into a therapeutic benefit.
Major
Summary and perspectives
Solid tumor masses typically exhibit abnormal blood vessel networks associated with heterogeneous blood flow. A consequence of the spatial and temporal heterogeneity of the microcirculation is a failure to provide adequate and homogeneous nutritional support to all regions of the tumor. Cancer cells existing in areas of poor oxygenation, acidic pH, and high interstitial pressure not only display resistance to radiation and chemotherapy but emerging evidence suggests that such microenvironmental
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
The authors' work is supported by the National Cancer Institute (Public Health Service grant R01 CA169300) as well as the Danish Cancer Society and the Danish Council for Independent Research: Medical Sciences.
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