title: Carbonic anhydrase IX from cancer-associated fibroblasts drives epithelial-mesenchymal transition in prostate carcinoma cells.
abstract: Extracellular acidification, a mandatory feature of several malignancies, has been mainly correlated with metabolic reprogramming of tumor cells toward Warburg metabolism, as well as to the expression of carbonic anydrases or proton pumps by malignant tumor cells. We report herein that for aggressive prostate carcinoma, acknowledged to be reprogrammed toward an anabolic phenotype and to upload lactate to drive proliferation, extracellular acidification is mainly mediated by stromal cells engaged in a molecular cross-talk circuitry with cancer cells. Indeed, cancer-associated fibroblasts, upon their activation by cancer delivered soluble factors, rapidly express carbonic anhydrase IX (CA IX). While expression of CAIX in cancer cells has already been correlated with poor prognosis in various human tumors, the novelty of our findings is the upregulation of CAIX in stromal cells upon activation. The de novo expression of CA IX, which is not addicted to hypoxic conditions, is driven by redox-based stabilization of hypoxia-inducible factor-1. Extracellular acidification due to carbonic anhydrase IX is mandatory to elicit activation of stromal fibroblasts delivered metalloprotease-2 and -9, driving in cancer cells the epithelial-mesenchymal transition epigenetic program, a key event associated with increased motility, survival and stemness. Both genetic silencing and pharmacological inhibition of CA IX (with sulfonamide/sulfamides potent inhibitors) or metalloprotease-9 are sufficient to impede epithelial-mesenchymal transition and invasiveness of prostate cancer cells induced by contact with cancer-associated fibroblasts. We also confirmed in vivo the upstream hierarchical role of stromal CA IX to drive successful metastatic spread of prostate carcinoma cells. These data include stromal cells, as cancer-associated fibroblasts as ideal targets for carbonic anhydrase IX-directed anticancer therapies.
authors: Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Tuscany, Italy.
authors: Tania
authors: T
authors: Fiaschi
authors: Elisa
authors: E
authors: Giannoni
authors: Maria Letizia
authors: ML
authors: Taddei
authors: Paolo
authors: P
authors: Cirri
authors: Alberto
authors: A
authors: Marini
authors: Gianfranco
authors: G
authors: Pintus
authors: Cristina
authors: C
authors: Nativi
authors: Barbara
authors: B
authors: Richichi
authors: Andrea
authors: A
authors: Scozzafava
authors: Fabrizio
authors: F
authors: Carta
authors: Eugenio
authors: E
authors: Torre
authors: Claudiu T
authors: CT
authors: Supuran
authors: Paola
authors: P
authors: Chiarugi
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014183:Transplantation, Heterologous; D015854:Up-Regulation
chemical_list: D000951:Antigens, Neoplasm; D051793:Hypoxia-Inducible Factor 1; D034741:RNA, Small Interfering; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases
keywords: acidity; cancer-associated fibroblasts; carbonic anhydrase IX; epithelial-mesenchymal transition; prostate cancer
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