Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid
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 ext...
| Main Authors: | , , , , , |
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| Format: | Journal article |
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National Academy of Sciences
2016
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| _version_ | 1797106107734294528 |
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| author | Hulikova, A Black, N Hsia, L Wilding, J Bodmer, W Swietach, P |
| author_facet | Hulikova, A Black, N Hsia, L Wilding, J Bodmer, W Swietach, P |
| author_sort | Hulikova, A |
| collection | OXFORD |
| description | 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 stromal myofibroblasts (colon cancer-derived Hs675.T, intestinal InMyoFib, embryonic colon-derived CCD-112-CoN), skin fibroblasts (NHDFAd) and colorectal cancer (CRC) cells (HCT116, HT29) grown in mono- or co-culture. Expression of the acid-loading transporter anion exchanger 2 (AE2; SLC4A2 product) was detected in myofibroblasts and fibroblasts, but not in CRC cells. Compared to CRCs, 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 CRCs, 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 NHDFAd and CCD-112-CoN cells was strengthened with TGFβ1. In contrast, acid-transmission was absent between CRCs, 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 biological functions. |
| first_indexed | 2024-03-07T06:57:01Z |
| format | Journal article |
| id | oxford-uuid:fe7741e6-b793-4a78-b1dc-0f6bd63d64fe |
| institution | University of Oxford |
| last_indexed | 2024-03-07T06:57:01Z |
| publishDate | 2016 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | oxford-uuid:fe7741e6-b793-4a78-b1dc-0f6bd63d64fe2022-03-27T13:36:50ZStromal uptake and transmission of acid is a pathway for venting cancer cell-generated acidJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fe7741e6-b793-4a78-b1dc-0f6bd63d64feSymplectic Elements at OxfordNational Academy of Sciences2016Hulikova, ABlack, NHsia, LWilding, JBodmer, WSwietach, PProliferation 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 stromal myofibroblasts (colon cancer-derived Hs675.T, intestinal InMyoFib, embryonic colon-derived CCD-112-CoN), skin fibroblasts (NHDFAd) and colorectal cancer (CRC) cells (HCT116, HT29) grown in mono- or co-culture. Expression of the acid-loading transporter anion exchanger 2 (AE2; SLC4A2 product) was detected in myofibroblasts and fibroblasts, but not in CRC cells. Compared to CRCs, 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 CRCs, 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 NHDFAd and CCD-112-CoN cells was strengthened with TGFβ1. In contrast, acid-transmission was absent between CRCs, 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 biological functions. |
| spellingShingle | Hulikova, A Black, N Hsia, L Wilding, J Bodmer, W Swietach, P Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid |
| title | Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid |
| title_full | Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid |
| title_fullStr | Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid |
| title_full_unstemmed | Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid |
| title_short | Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid |
| title_sort | stromal uptake and transmission of acid is a pathway for venting cancer cell generated acid |
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