Acid-mediated tumor invasion: a multidisciplinary study.

The acid-mediated tumor invasion hypothesis proposes altered glucose metabolism and increased glucose uptake, observed in the vast majority of clinical cancers by fluorodeoxyglucose-positron emission tomography, are critical for development of the invasive phenotype. In this model, increased acid production due to altered glucose metabolism serves as a key intermediate by producing H(+) flow along concentration gradients into adjacent normal tissue. This chronic exposure of peritumoral normal tissue to an acidic microenvironment produces toxicity by: (a) normal cell death caused by the collapse of the transmembrane H(+) gradient inducing necrosis or apoptosis and (b) extracellular matrix degradation through the release of cathepsin B and other proteolytic enzymes. Tumor cells evolve resistance to acid-induced toxicity during carcinogenesis, allowing them to survive and proliferate in low pH microenvironments. This permits them to invade the damaged adjacent normal tissue despite the acid gradients. Here, we describe theoretical and empirical evidence for acid-mediated invasion. In silico simulations using mathematical models provide testable predictions concerning the morphology and cellular and extracellular dynamics at the tumor-host interface. In vivo experiments confirm the presence of peritumoral acid gradients as well as cellular toxicity and extracellular matrix degradation in the normal tissue exposed to the acidic microenvironment. The acid-mediated tumor invasion model provides a simple mechanism linking altered glucose metabolism with the ability of tumor cells to form invasive cancers.

The glycolytic phenotype in carcinogenesis and tumor invasion: insights through mathematical models.

Malignant cells characteristically exhibit altered metabolic patterns when compared with normal mammalian cells with increased reliance on anaerobic metabolism of glucose to lactic acid even in the presence of abundant oxygen. The inefficiency of the anaerobic pathway is compensated by increased glucose flux, a phenomenon first noted by Otto Warburg approximately 80 years ago and currently exploited for 2-fluoro-2-deoxy-D-glucose-positron emission tomography imaging in clinical radiology. The latter has demonstrated the glycolytic phenotype is a near-universal phenomenon in human cancers. The potential role of the glycolytic phenotype in facilitating tumor invasion has been investigated through mathematical models of the tumor-host interface. Modified cellular automaton and diffusion reaction models demonstrate protons will diffuse from the tumor into peritumoral normal tissue subjecting nontransformed cells adjacent to the tumor edge to an extracellular pH significantly lower than normal. This leads to normal cell death via p53-dependent apoptosis pathways, as well as degradation of the interstitial matrix, loss of intercellular gap junctions, enhanced angiogenesis, and inhibition of the host immune response to tumor antigens. Transformed cells maintain their proliferative capacity in acidic extracellular pH because of mutations in p53 or some other component in the apoptosis pathways. This allows tumor cells to remain proliferative and migrate into the peritumoral normal tissue producing the invasive phenotype. Mathematical models of invasive cancer based on tumor-induced acidification are consistent with extant data on tumor microenvironment and results from clinical positron emission tomography imaging, including the observed correlation between tumor invasiveness and glucose utilization. Novel treatment approaches focused on perturbation of the tumor microenvironment are predicted from the mathematical models and are supported by recent clinical data demonstrating the benefits of azotemia and metabolic acidosis in survival of patients with metastatic renal cancer. The evolutionary basis for adoption of the glycolytic phenotype during carcinogenesis remains unclear because it appears to confer significant competitive disadvantages on the tumor cells due to of inefficient energy production and expenditure of resources to remove the acid byproducts. We propose that the glycolytic phenotype represents a successful adaptation to environmental selection parameters because it confers the ability to invade. That is, the glycolytic phenotype allows the cell to move from the microenvironment of a premalignant lesion to adjacent normal tissue. There it competes with normal cells that are less fit than the populations within the tumor in a microenvironment of relative substrate abundance. The consequent unrestrained proliferation allows the glycolytic phenotype to emerge simultaneous with the transition from a premalignant lesion to an invasive cancer.

The possible role of postoperative azotemia in enhanced survival of patients with metastatic renal cancer after cytoreductive nephrectomy.

Cytoreductive nephrectomy prior to systemic therapy significantly increases survival in patients with metastatic renal cancer. This result is generally ascribed to the benefits of resection of the primary tumor including reduction of tumor burden, removal of a source for growth factors and metastases, and enhanced immune response. On the basis of mathematical models of tumor invasion, we propose that the observed effects of cytoreductive nephrectomy may be caused by resection of the kidney rather than the cancer. The models predict that the graded metabolic acidosis associated with mild renal failure after unilateral nephrectomy may alter the dynamics of the tumor-host interface sufficiently to reduce and even reverse the rate of invasion. A review of patient data from the surgical arm of the Southwest Oncology Group (SWOG) 8949(2) trial demonstrates significantly improved survival in patients who experienced postoperative increase in blood urea nitrogen (BUN) and creatinine compared with those who did not (17-month survival versus 4-month survival; P = 0.0007). This is generally consistent with the predictions of the mathematical models. If confirmed, these results suggest novel and broadly applicable tumor therapies.