Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression

Abstract

Carcinogenesis is a complex, multistep, multipath process often described as "somatic evolution". Conventional models of cancer progression are typically based on the genetic and epigenetic changes observed in malignant and premalignant tumors. We have explored an alternative approach that emphasizes the selection forces within adaptive landscapes governing growth and evolution in in situ, microinvasive, and metastatic cancers. In each environment, specific barriers to proliferation act as strong selection forces that determine the optimal phenotypic properties that permit tumor growth and invasion. Thus, the phenotypic properties or "hallmarks" of cancer can be viewed as successful adaptations to these microenvironmental selection forces. In turn, these selection pressures are not static but will dynamically change as a result of tumor population growth and evolution. Here, we emphasize the role of hypoxia and acidosis in the progression of tumor from in situ to invasive cancer. This is a consequence of early tumor cell proliferation on epithelial surfaces, which are separated from the underlying blood supply by the intact basement membrane. As tumor cells proliferate further away from the basement membrane, the diffusion-reaction kinetics of substrate and metabolite flow to and from the blood vessels result in regional hypoxia and acidosis. Cellular adaptation to the former include upregulation of glycolysis and to the latter include upregulation of Na+/H+ exchangers (NHE1) and other acid-regulating proteins such as carbonic anhydrase. We propose this phenotype is critical for subsequent malignant growth of primary and metastatic cancers.

Figure 1

Immunohistochemical staining for GLUT-1 in ductal carcinoma in situ showing evidence of regional hypoxia with central necrosis and upregulation of GLUT-1 in cells furthest from the basement membrane

Figure 2

A Model of Carcinogenesis, adapted from Gillies & Gatenby (2007). Carcinogenesis is presented with tumorigenic barriers and proposed timing of hallmark events.^2,4 The specific order of occurrence for each carcinogenic hallmark may differ from cancer to cancer. Although not originally listed as a hallmark event, diminished DNA repair is included here because it can be considered a necessary step for subsequent carcinogenesis.

Figure 3

Diffusion of O₂ From a Blood Vessel To Surrounding Tissue Extends to a Maximal Distance (r_crit) Due To Loss of O₂ From Metabolism. Extrapolation of r_crit along the length of the vessel forms a cylinder representing the functional extent of oxygenation by the vessel.

Figure 4

Diagram of the “Redox Switch Hypothesis”, adapted from Cerdan et al. (2006). Briefly, lactate dehydrogenase (LDH) competes with GAPdH for NAD⁺, following accumulation of cytosolic lactate under anaerobic conditions. This upregulates lactate metabolism and reduces or eliminates glycolytic flux.

Figure 5

Transactivation By C-myc. C-myc heterodimerizes with Max to activate or decrease expression of genes involved in several cellular processes.

Figure 6

HIF-1α Degradation in Normoxia by the Ubiquitin-Proteasomal Pathway, adapted from Ke and Costa (2006). During normoxia, HIF-1α is hydroxylated by PHD and FIH, which promotes the binding of VHL ubiquitin ligase. HIF-1α is thus is rapidly degraded via the ubiquitin-proteasome pathway. Under hypoxic conditions, FIH and PHD are inactive. Instead, HIF-1α is phosphorylated by MAPK and bound by CBP/p300, inducing heterodimerization with HIF-1β and transactivation of a variety of genes.

Figure 7

Transactivation By HIF. HIF-1α heterodimerizes with HIF-1β to activate families of genes that may have implications for CIS maturation and the Warburg Effect.