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Abstract
The acidic tumor microenvironment modifies malignant cell behavior. Here, we study consequences of the microenvironment in breast carcinomas. Beginning at carcinogen-based breast cancer induction, we supply either regular or NaHCO3-containing drinking water to female C57BL/6j mice. We evaluate urine and blood acid-base status, tumor metabolism (microdialysis sampling), and tumor pH (pH-sensitive microelectrodes) in vivo. Based on freshly isolated epithelial organoids from breast carcinomas and normal breast tissue, we assess protein expression (immunoblotting, mass spectrometry), intracellular pH (fluorescence microscopy), and cell proliferation (bromodeoxyuridine incorporation). Oral NaHCO3 therapy increases breast tumor pH in vivo from 6.68 ± 0.04 to 7.04 ± 0.09 and intracellular pH in breast epithelial organoids by ~0.15. Breast tumors develop with median latency of 85.5 ± 8.2 days in NaHCO3-treated mice vs. 82 ± 7.5 days in control mice. Oral NaHCO3 therapy does not affect tumor growth, histopathology or glycolytic metabolism. The capacity for cellular net acid extrusion is increased in NaHCO3-treated mice and correlates negatively with breast tumor latency. Oral NaHCO3 therapy elevates proliferative activity in organoids from breast carcinomas. Changes in protein expression patterns—observed by high-throughput proteomics analyses—between cancer and normal breast tissue and in response to oral NaHCO3 therapy reveal complex influences on metabolism, cytoskeleton, cell-cell and cell-matrix interaction, and cell signaling pathways. We conclude that oral NaHCO3 therapy neutralizes the microenvironment of breast carcinomas, elevates the cellular net acid extrusion capacity, and accelerates proliferation without net effect on breast cancer development or tumor growth. We demonstrate unexpected pro-neoplastic consequences of oral NaHCO3 therapy that in breast tissue cancel out previously reported anti-neoplastic effects.
Highlights
The acidic tumor microenvironment is a hallmark of solid cancer tissue with multifaceted consequences for cancer cells, adjacent normal cells, and their interactions [1,2]
Na+, HCO3 – -cotransporter NBCn1 (Slc4a7) is upregulated in human and murine breast cancer tissue compared to normal breast tissue; and acting in parallel with the Na+ /H+ -exchanger isoform 1 (NHE1, Slc9a1), NBCn1 is the predominant path for net acid extrusion from breast cancer cells [8,9,10,11]
We identify marked differences in protein expression patterns related to cell-cell and cell-matrix interactions, cytoskeletal dynamics, and immune-related functions between organoids freshly isolated from breast cancer tissue and matched normal breast tissue (Figure 1F and Figure S1A)
Summary
The acidic tumor microenvironment is a hallmark of solid cancer tissue with multifaceted consequences for cancer cells, adjacent normal cells, and their interactions [1,2]. Enhanced metabolic acid production in cancer tissue is a consequence of accelerated glycolysis and/or oxidative phosphorylation that provide energy and chemical intermediates for cancer cell proliferation [3]. Cancer cells export the increased acid load to the extracellular space via acid-base transporters in their cell membranes [4,5,6]. Acid-base transport processes across membranes, within the cytoplasm, and through the tortuous extracellular space can be accelerated by carbonic anhydrases that catalyze the reaction CO2 + OH− HCO3 − [14,15,16]. The functional consequences of carbonic anhydrases have hitherto been studied mostly in model systems and need to be confirmed in breast cancer tissue
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