Acid-Mediated Tumor Invasion: a Multidisciplinary Study

Abstract

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 acidinduced 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.

Mitochondria and cancer: is there a morphological connection?

“…Firstly, it enables cancer cells to adapt to hypoxic conditions as the premalignant lesion grows progressively further from the blood supply. Secondly, the glycolytic phenotype contributes to the acidification of tumour microenvironment, which facilitates tumour invasion (Gatenby and Gawlinski, 1996;Schornack and Gillies, 2003). This metabolic transition towards glycolysis is also seen in human cancer cell lines such as Hela cells, in which minor amounts of glucose are prone to the TCA cycle, the majority being converted to lactate (Reitzer et al, 1979).…”

Phenotypic changes of acid-adapted cancer cells push them toward aggressiveness in their evolution in the tumor microenvironment

“…8 Using dorsal window chambers, we have demonstrated that acidic environments promote tumor invasion and growth by degrading adjacent extracellular matrix]. 9,10 Thus, we view the intratumoral environment as "niche engineering" wherein cancer cells, in response to Darwinian dynamics, generate an environment that promotes their own growth and invasion 11 at the expense of the stromal cells into which they invade. Acidosis also inhibits anti-tumor immunity and promotes immune editing.…”

“…12 From these observations, we have proposed the "acid-mediated invasion" model, wherein tumor-derived acid promotes remodeling of the extracellular matrix, while cancer cells contemporaneously become adapted and more resistant to acidity, compared to the stromal cells into which they invade. 10 However, the mechanism by which tumor cells adapt to this chronic acidosis is not yet fully known. This is a critically important question, as it is virtually axiomatic that, in order to thrive, cells in tumors must develop mechanisms of defense that render them insensitive to this acid challenge.…”

BAX inhibitor-1 enhances cancer metastasis by altering glucose metabolism and activating the sodium-hydrogen exchanger: the alteration of mitochondrial function

“…Alterations of glucose metabolism regulate cancer metastasis by high glucose uptake, high lactate formation, low extracellular pH (pH e ) and reduction of intratumoral pH (Bhujwalla et al, 2002;Schornack and Gillies, 2003;Gatenby and Gillies, 2004;Gatenby et al, 2006). The acidic environment is produced by the activity of ion channels and transporters such as Na þ /H þ or Cl/HCO 3 exchangers (Klein et al, 2000;Saadoun et al, 2005).…”