Abstract
Solid tumors are composed of both cancer cells and various types of accessory cells, mainly fibroblasts, that collectively compose the so called tumor-microenvironment. Cancer-associated fibroblasts have been described to actively participate in cancer progression by establishing a cytokine-mediated as well as metabolic crosstalk with cancer cells. In the present paper we show that activated human fibroblasts are able to boost tumor cells proliferation and that this effect is greatly dependent on stromal carbonic anhydrase IX (CA IX) activity. In fact fibroblasts show a strong upregulation of CA IX expression upon activation by cancer cells, while CA IX products, protons and bicarbonate, exert differential effects on cancer cells proliferation. While acidification of extracellular pH, a typical condition of rapidly growing solid tumors, is detrimental for tumor cells proliferation, bicarbonate, through its organication, supplies cancer cells with intermediates useful to sustain their high proliferation rate. Here we propose a new kind of fibroblasts/tumor cells crosstalk within tumor microenvironment, mediated by stromal CA IX products, aimed to favor cancer cells growth, opening new perspectives on CA IX role in tumor microenvironment.
Highlights
Solid tumors are a collection of highly heterogeneous cancer cells but a very complex tissue composed by both cellular and non-cellular components, commonly defined as the tumor microenvironment (TM)
We found that tumor cells kept in hypoxia acidify the extracellular medium more than normoxic cells (Figure 1A-C) and that, in coculture, the protons release in the extracellular medium is greater than the sum of single culture cell proton release (Figure 1B-D)
This suggests that the interplay between cancer and stromal cells affects important changes in normal and/or in tumor cells metabolism leading to an “extra” acidification of the medium
Summary
Solid tumors are a collection of highly heterogeneous cancer cells but a very complex tissue composed by both cellular and non-cellular components, commonly defined as the tumor microenvironment (TM). The transdifferentiation of CAFs is mediated by numerous growth factors and cytokines secreted by cancer cells such as Tumour Growth Factor-1 (TGF-β1) [2], PDGF-α/β [3] and interleukin (IL)-6 [4]. Many ways in which CAFs could support cancer progression have been described: The tumor microenvironment is markedly different from that of normal tissues regarding important extracellular parameters such as extracellular pH (pHe) and oxygen tension (pO2). The combined effect of defective vascularization and the high metabolic activity of cancer cells leads to the consequence that tumor microenvironment is both relatively acidic and hypoxic compared to normal tissue [11,12]. The stringent control on cellular pHi, mandatory for cells survival [13], is mediated by different types of pHi regulating proteins such as: Na/H exchanger-1, anion exchangers, Na/bicarbonate cotransporters, monocarboxylate transporters and carbonic anhydrases (CAs) [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
