Bicarbonate Increases Tumor pH and Inhibits Spontaneous Metastases

By I. Robey, B. Baggett, N. Kirkpatrick, D. Roe, J. Dosescu, Bonnie F. Sloane, Arig Ibrahim Hashim, D. Morse, N. Raghunand, Robert A. Gatenby and 1 more. Cancer Research, 2009

615 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Spectroscopy

View Paper: https://www.semanticscholar.org/paper/ba4c8853b6ead9a05c6b0a68bd009412f95eb753

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

Citations in the corpus

The Acidic Tumor Microenvironment as a Driver of Cancer. (2019, background): “, HCO3− or Tris-base) are provided orally in order to neutralize the extracellular tumor microenvironment (137, 140), has shown promise as a maneuver that enhances immune-mediated responses against xenograft tumors (141).”
Acidity generated by the tumor microenvironment drives local invasion (2013, methodology): “We have previously shown that a variety of buffers including bicarbonate, Tris, lysine, and imidazoles, can neutralize tumor pHe and inhibit tumor invasion and metastasis (8, 24).”
Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer (2009, background): “Recently, Gatenby and colleagues gave mice NaHCO3 in their drinking water and reported an alkalinized tumour microenvironment and reduce metastatic formation in tumour bearing mice [263].”
Targeting metabolic transformation for cancer therapy (2010, methodology): “Indeed, neutralizing extra-tumoural pH using bicarbonate was recently shown to decrease the metastatic potentialof tumour cells in both orthotopic (mammary fat pad) and a metastatic (intra-splenic injection) tumour model”
Acidic extracellular microenvironment and cancer (2013, background): “Pretreatment of the tumor cells in an acidic medium induces production of proteinases (MMPs and cathepsins) and proangiogenic factors (VEGF-A and IL-8) and promotes experimental metastasis to the lung after injection into the tail vein of nude mice [5]; elevation of pH by one unit following injectio”
Dysregulated pH: a perfect storm for cancer progression (2011, background): “The potential of modulating pH e to reduce tumour cell metastasis was recently shown by Robey et al”