ReviewAdaptation to hypoxia and acidosis in carcinogenesis and tumor progression
Introduction
Invasive cancer develops over a prolonged period through accumulation of multiple heritable genetic changes—a process often characterized as “somatic evolution”. Early researchers inducing skin tumors in animal models noted that tumorigenesis progresses through distinct and predictable phases. The first step (initiation) follows application of a mutagenic agent such as radiation. This produces no visible tissue change and the resulting phenotype is usually not distinguishable from normal cells. Nevertheless, the initiation step permanently predisposes the treated skin to development of cancer, but initiation alone is typically insufficient for tumor formation and exposure of the skin to irritants such as tar (the promotion step) is required to induce growth of visible lesions. This growth, however, remains self-limited and the pre-cancerous carcinomas will typically regress after withdrawal of the promoting agent. Development of an invasive cancer requires additional prolonged, repeated stimulation by non-carcinogenic, genotoxic agents, such as turpentine (the progression step) [1].
Here, we will review carcinogenesis as a multistage process, and consider the metabolic constraints placed on a developing pre-invasive tumor, as well as the subsequent adaptations that are proposed to occur, in a predictable fashion, in the evolution of an invasive cancer.
In healthy tissue, constraints to tumorigenesis exist in the form of hard-wired barriers that prevent disruption of tissue architecture and function by inappropriate cellular proliferation. These controls include highly regulated activation by specific pro-growth signals and growth-inhibitory barriers through anoikis and interactions with other cells and the extracellular matrix. Finally, cellular hyperproliferation on epithelial surfaces creates a spatially limited milieu – as with a pre-invasive carcinoma in situ (CIS), discussed below – that will increase local metabolic demands beyond the sustainability of surrounding tissue causing a decrease in concentrations of available nutrients and a build-up of potentially toxic waste products (Fig. 1) [2], [3].
During the course of carcinogenesis, these barriers to proliferation must be overcome to permit the unconstrained cell growth characteristic of cancer. Hanahan and Weinberg [4] proposed that these obstacles would direct the progression of carcinogenesis such that all carcinomas – regardless of their diverse tissue origins and specific genomic changes – would evolve at least six predictable hallmark features that must be present in any carcinoma in order to sustain tumor growth: (1) insensitivity to anti-growth signals, (2) evasion of apoptosis, (3) self-sufficient growth signals, (4) limitless replicative potential (immortalization), (5) sustained angiogenesis, and (6) invasion and metastasis. Gatenby and Gillies [3] expanded upon these six hallmarks by proposing two more: (1) evasion of anoikis—cell death signals mediated by loss of cell–ECM contact, and (2) increased glucose consumption through increased glycolysis, and resistance to the toxicity of subsequent local acidification. They also emphasized the critical role of a sequence of specific external (microenvironmental) obstacles that must be overcome for carcinogenesis to proceed. These cancer hallmarks can be mapped onto the observed progression from normal tissue to metastatic cancer to produce a teleologically derived model for carcinogenesis (Fig. 2). A key prediction of this model is that regions of hypoxia and acidosis will inevitably develop in CIS lesions and that adaptations to these microenvironmental forces are critical for the transition from in situ to invasive cancer. As outlined in Fig. 1, this previously unrecognized era in carcinogenesis is due to the separation of proliferating intraluminal tumor cells from the underlying blood vessels by the intact basement membrane. This constrains delivery of substrates to diffusion over increasingly long distances as the tumor expands into the lumen. The diffusion-reaction kinetics are predicted to result in hypoxia and acidosis in tumor regions even within a few cell layers of the basement membrane.
Section snippets
Diffusion-reaction models of substrate flow
To first test the hypothesized model of CIS maturation, we use mathematical models to examine substrate flow in pre-invasive tumors. As demonstrated in Fig. 1, tumor cells in CIS grow away from the basement membrane thus increasing their distance from the blood vessels which remain on the opposite side of the membrane. The diffusion of O2 from blood vessel to surrounding tissue (Fig. 3) can be mathematically modeled using a reaction-diffusion equation based on Fick's second law of diffusion.
Models of carcinogenesis
A number of theoretical models of all or some stages of carcinogenesis exist. These include the initiation–promotion–progression approach (described above) derived largely from empirical observations in skin carcinogenesis. The Folkman model focuses on the transition from non-angiogenic to angiogenic phenotype in the corresponding transition from limited to unrestricted tumor growth [36]. Work by Bissell and Nelson [37], while never formalized in an explicit theoretic model, emphasizes the
Conclusion
The transition from pre-invasive to invasive carcinoma may be closely linked to the CIS microenvironment. Though each carcinoma arises out of a unique series of genomic changes that induce a number of early hallmarks of cancer, the process of carcinogenesis converges on the development of hypoxia and acidosis in a bounded, avascular tumor that occurs as a result of increased cell number and density in a limited, avascular space. This unique microenvironment creates a harsh adaptive landscape
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