Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Tuscany, Italy.
Cell Cycle. 2013 Jun 1;12(11):1791-801. doi: 10.4161/cc.24902. Epub 2013 May 8.
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.
细胞外酸化是几种恶性肿瘤的一个强制性特征，主要与肿瘤细胞向沃伯格代谢的代谢重编程以及碳酸酐酶或质子泵的表达有关。我们在此报告，对于侵袭性前列腺癌，公认的是向合成代谢表型重新编程，并上传乳酸以驱动增殖，细胞外酸化主要是由与癌细胞发生分子交叉对话电路的基质细胞介导的。事实上，在被癌症传递的可溶性因子激活后，癌症相关成纤维细胞会迅速表达碳酸酐酶 IX（CAIX）。虽然 CAIX 在癌细胞中的表达已经与各种人类肿瘤的不良预后相关，但我们发现的新内容是在激活时 CAIX 在基质细胞中的上调。CAIX 的新表达不是依赖于缺氧条件，而是由基于氧化还原的缺氧诱导因子-1 的稳定驱动的。由于碳酸酐酶 IX 的存在而导致的细胞外酸化对于引发基质成纤维细胞的激活是必需的，这些成纤维细胞可以分泌金属蛋白酶-2 和 -9，从而在癌细胞中引发上皮-间充质转化的表观遗传程序，这是与增加的迁移、存活和干细胞特性相关的关键事件。基因沉默和 CAIX 的药理学抑制（使用磺胺类/磺胺类有效抑制剂）或金属蛋白酶-9 都足以阻止与癌症相关的成纤维细胞接触诱导的前列腺癌细胞的上皮-间充质转化和侵袭性。我们还在体内证实了基质 CAIX 在上游驱动前列腺癌细胞成功转移扩散的分层作用。这些数据包括基质细胞，因为癌症相关成纤维细胞是碳酸酐酶 IX 导向的抗癌治疗的理想靶点。
