Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Cancer Discov. 2012 Sep;2(9):840-55. doi: 10.1158/2159-8290.CD-12-0101. Epub 2012 Jul 3.
Mesenchymal cells of the tumor-associated stroma are critical determinants of carcinoma cell behavior. We focus here on interactions of carcinoma cells with mesenchymal stem cells (MSC), which are recruited to the tumor stroma and, once present, are able to influence the phenotype of the carcinoma cells. We find that carcinoma cell-derived interleukin-1 (IL-1) induces prostaglandin E(2) (PGE(2)) secretion by MSCs. The resulting PGE(2) operates in an autocrine manner, cooperating with ongoing paracrine IL-1 signaling, to induce expression of a group of cytokines by the MSCs. The PGE(2) and cytokines then proceed to act in a paracrine fashion on the carcinoma cells to induce activation of β-catenin signaling and formation of cancer stem cells. These observations indicate that MSCs and derived cell types create a cancer stem cell niche to enable tumor progression via release of PGE(2) and cytokines.
Although PGE2 has been implicated time and again in fostering tumorigenesis, its effects on carcinoma cells that contribute specifically to tumor formation are poorly understood. Here we show that tumor cells are able to elicit a strong induction of the COX-2/microsomal prostaglandin-E synthase-1 (mPGES-1)/PGE(2) axis in MSCs recruited to the tumor-associated stroma by releasing IL-1, which in turn elicits a mesenchymal/stem cell–like phenotype in the carcinoma cells.
肿瘤相关基质中的间充质细胞是癌细胞行为的关键决定因素。我们在这里重点关注癌细胞与间充质干细胞（MSC）的相互作用，MSC 被招募到肿瘤基质中，一旦存在，就能够影响癌细胞的表型。我们发现癌细胞衍生的白细胞介素-1（IL-1）诱导 MSC 分泌前列腺素 E2（PGE2）。由此产生的 PGE2 以自分泌方式作用，与持续的旁分泌 IL-1 信号协同作用，诱导 MSC 表达一组细胞因子。然后，PGE2 和细胞因子以旁分泌方式作用于癌细胞，诱导 β-连环蛋白信号的激活和癌症干细胞的形成。这些观察结果表明，MSC 和衍生的细胞类型通过释放 PGE2 和细胞因子，为肿瘤进展创造了癌症干细胞生态位。
尽管 PGE2 一再被牵连促进肿瘤发生，但它对特定于肿瘤形成的癌细胞的影响知之甚少。在这里，我们表明，肿瘤细胞能够通过释放白细胞介素-1（IL-1）强烈诱导募集到肿瘤相关基质中的 MSC 中的 COX-2/微粒体前列腺素 E 合酶-1（mPGES-1）/PGE2 轴，这反过来又在癌细胞中引发间充质/干细胞样表型。
