ArticleProceedings of the National Academy of Sciences of the United States of America2016
Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 47 citations in OpenAlex.
- AKAP12-LMOD1 signaling defines stromal CAF activation and epithelial junction loss in colorectal cancer.Scientific reports · 2026Article
- A Biomimetic Buffering Hydrogel Scaffold for Long-Term Culture of Patient-Derived Tumor Organoids.Advanced healthcare materials · 2026Article
- GJA4 expressed on cancer associated fibroblasts (CAFs)-A 'promoter' of the mesenchymal phenotype.Translational oncology · 2024Article
- Acid-base transporters in the context of tumor heterogeneity.Pflugers Archiv : European journal of physiology · 2024Review
- Phenotypic screen of sixty-eight colorectal cancer cell lines identifies CEACAM6 and CEACAM5 as markers of acid resistance.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Tumor perfusion enhancement by microbubbles ultrasonic cavitation reduces tumor glycolysis metabolism and alleviate tumor acidosis.Frontiers in oncology · 2024Article
- How protons pave the way to aggressive cancers.Nature reviews. Cancer · 2023Review
- Metabolic targeting of malignant tumors: a need for systemic approach.Journal of cancer research and clinical oncology · 2023Review
- The Multifaceted Role of Connexins in Tumor Microenvironment Initiation and Maintenance.Biology · 2023Review
- Review
- An Analysis Regarding the Association Between Connexins and Colorectal Cancer (CRC) Tumor Microenvironment.Journal of inflammation research · 2022Article
- How Reciprocal Interactions Between the Tumor Microenvironment and Ion Transport Proteins Drive Cancer Progression.Reviews of physiology, biochemistry and pharmacology · 2022Review
- Ion Channels, Transporters, and Sensors Interact with the Acidic Tumor Microenvironment to Modify Cancer Progression.Reviews of physiology, biochemistry and pharmacology · 2022Review
- Hypoxia and Extracellular Acidification as Drivers of Melanoma Progression and Drug Resistance.Cells · 2021Review
- Role of Stromal Cells in Determining Tumor and Cancer Stem Cell Behaviors and Therapeutic Response.Cancers · 2020Article
- Discovered differentially expressed lncRNA AC010973.2 can act as a diagnostic and prognostic biomarker for colon adenocarcinoma.Translational cancer research · 2020Article
- Monocarboxylate transporters in cancer.Molecular metabolism · 2020Review
- Spatiotemporal pH Heterogeneity as a Promoter of Cancer Progression and Therapeutic Resistance.Cancers · 2019Review
- Cancer Metabolism Drives a Stromal Regenerative Response.Cell metabolism · 2019Review
- Acid-Induced Downregulation of ASS1 Contributes to the Maintenance of Intracellular pH in Cancer.Cancer research · 2019Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Proliferation and invasion of cancer cells require favorable pH, yet potentially toxic quantities of acid are produced metabolically. Membrane-bound transporters extrude acid from cancer cells, but little is known about the mechanisms that handle acid once it is released into the poorly perfused extracellular space. Here, we studied acid handling by myofibroblasts (colon cancer-derived Hs675.T, intestinal InMyoFib, embryonic colon-derived CCD-112-CoN), skin fibroblasts (NHDF-Ad), and colorectal cancer (CRC) cells (HCT116, HT29) grown in monoculture or coculture. Expression of the acid-loading transporter anion exchanger 2 (AE2) (SLC4A2 product) was detected in myofibroblasts and fibroblasts, but not in CRC cells. Compared with CRC cells, Hs675.T and InMyoFib myofibroblasts had very high capacity to absorb extracellular acid. Acid uptake into CCD-112-CoN and NHDF-Ad cells was slower and comparable to levels in CRC cells, but increased alongside SLC4A2 expression under stimulation with transforming growth factor β1 (TGFβ1), a cytokine involved in cancer-stroma interplay. Myofibroblasts and fibroblasts are connected by gap junctions formed by proteins such as connexin-43, which allows the absorbed acid load to be transmitted across the stromal syncytium. To match the stimulatory effect on acid uptake, cell-to-cell coupling in NHDF-Ad and CCD-112-CoN cells was strengthened with TGFβ1. In contrast, acid transmission was absent between CRC cells, even after treatment with TGFβ1. Thus, stromal cells have the necessary molecular apparatus for assembling an acid-venting route that can improve the flow of metabolic acid through tumors. Importantly, the activities of stromal AE2 and connexin-43 do not place an energetic burden on cancer cells, allowing resources to be diverted for other activities.
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Registered trials
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