Bicarbonate Increases Tumor pH and Inhibits Spontaneous Metastases

Tuesday, 05/02/2013  |   Cancer Process, Herb or Compound  |  no comments


The external pH of solid tumors is acidic as a consequence of increased metabolism of glucose and poor perfusion. Acid pH has been shown to stimulate tumor cell invasion and metastasis in vitro and in cells before tail vein injection in vivo. The present study investigates whether inhibition of this tumor acidity will reduce the incidence of in vivo metastases. Here, we show that oral NaHCO3 selectively increased the pH of tumors and reduced the formation of spontaneous metastases in mouse models of metastatic breast cancer. This treatment regimen was shown to significantly increase the extracellular pH, but not the intracellular pH, of tumors by 31P magnetic resonance spectroscopy and the export of acid from growing tumors by fluorescence microscopy of tumors grown in window chambers. NaHCO3 therapy also reduced the rate of lymph node involvement, yet did not affect the levels of circulating tumor cells, suggesting that reduced organ metastases were not due to increased intravasation. In contrast, NaHCO3 therapy significantly reduced the formation of hepatic metastases following intrasplenic injection, suggesting that it did inhibit extravasation and colonization. In tail vein injections of alternative cancer models, bicarbonate had mixed results, inhibiting the formation of metastases from PC3M prostate cancer cells, but not those of B16 melanoma. Although the mechanism of this therapy is not known with certainty, low pH was shown to increase the release of active cathepsin B, an important matrix remodeling protease.
Robey IF, Baggett BK, Kirkpatrick ND, et al. Cancer Res 2009;69(6):2260–8. doi: 10.1158/0008-5472.CAN-07-5575

Acidity generated by the tumor microenvironment drives local Invasion
The pH of solid tumors is acidic due to increased fermentative metabolism and poor perfusion. It has been hypothesized that acid pH promotes local invasive growth and metastasis. The hypothesis that acid mediates invasion proposes that H+ diffuses from the proximal tumor microenvironment into adjacent normal tissues where it causes tissue remodeling that permits local invasion. In the current work, tumor invasion and peritumoral pH were monitored over time using intravital microscopy. In every case, the peritumoral pH was acidic and heterogeneous and the regions of highest tumor invasion corresponded to areas of lowest pH. Tumor invasion did not occur into regions with normal or near-normal pHe. Immunohistochemical analyses revealed that cells in the invasive edges expressed the glucose transporter GLUT-1 and the sodium-hydrogen exchanger NHE-1, both of which were associated with peritumoral acidosis. In support of the functional importance of our findings, oral administration of sodium bicarbonate was sufficient to increase peritumoral pH and inhibit tumor growth and local invasion in a preclinical model, supporting the acid-mediated invasion hypothesis.
Estrella V, Chen T, Lloyd M, et al. Cancer Res Published OnlineFirst January 3, 2013; doi:10.1158/0008-5472.CAN-12-2796

Tumor Cells Engineer Acidity to Drive Cell Invasion
Researchers at Moffitt Cancer Center and colleagues at Wayne State University School of Medicine investigated the acidity in solid tumors to determine if pH levels play a role in cancer cell invasion in surrounding tissues. They found that an acidic microenvironment can drive cancer cells to spread and propose that neutralizing pH would inhibit further invasion, providing a therapeutic opportunity to slow the progression of cancers.
Their study appeared in the Jan. 3 online release of Cancer Research, a publication of the American Association for Cancer Research.
According to the study’s corresponding author, Robert J. Gillies, Ph.D., chair of the Department of Cancer Imaging & Metabolism at Moffitt, acidity in solid tumors is the result of an increased fermentative metabolism combined with poor delivery of blood to tissues.
In this study, tumor invasion and pH were monitored in immunodeficient laboratory mice hosting a variety of tumors. “We monitored the test animals over time using microscopy and found that the highest regions of tumor invasion corresponded to areas with the lowest pH,” Gillies explained. “Tumor invasion did not occur in regions with normal or near normal pH levels. Furthermore, when we neutralized the acidity with oral sodium bicarbonate, the invasion was halted.”
Researchers proposed that the acidic pH of the tumor microenvironment represents a “niche engineering” strategy on the part of tumor cells, promoting invasion and growth of malignant tumors into surrounding tissue. Niche engineering is a concept in ecology describes how plants and animals alter their environment to in ways that promote their own growth and survival over their competitors. “We have long regarded cancers cells as an invading species,” said study co-author Robert Gatenby, M.D., chair of the Diagnostic Imaging Services and Integrated Mathematical Oncology departments at Moffitt.
A key to this process of adaptation and invasion is increased glucose metabolism in the tumor. “The vast majority of malignant tumors metabolize glucose at high rates,” Gillies said. “We have proposed that there is a direct, causative link between increased glucose metabolism and the ability of cancer cells to invade and metastasize.”
According to the research, elevated glucose metabolism is the cause of increased acidity in the tumor microenvironment. Most tumors develop an abnormal vascular network that tends to be poorly organized and leaky, disrupting blood flow and hampering the delivery of oxygen.
“This poorly organized vascular system has a two-fold effect on tumor acidity,” explained Gatenby. “First, it subjects tumor regions to poor perfusion, which restricts oxygen and increases the rate of glucose fermentation. Second, the poor perfusion hampers the ability to eliminate the resulting acids, resulting in very low pH in surrounding tissues.”
As tumor cells adapt to increasing acidity, niche engineering through normal cell death and new blood vessel formation occurs in the tumor and the immune response is suppressed.
“Tumor cells perform niche engineering by creating an acidic environment that is not toxic to the malignant cells but, through its negative effects on normal cells and tissues, promotes local invasion of malignant cells,” Gatenby said.
The researchers suggested that targeting this activity with buffers and other mechanisms aimed at increasing pH levels will likely provide a valuable alternative to traditional therapies focused entirely on killing tumor cells.

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