Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Cancer Sci. 2020 Apr;111(4):1047-1057. doi: 10.1111/cas.14346. Epub 2020 Mar 10.
The roles of cancer-associated fibroblasts (CAF) in the progression of various types of cancers are well established. CAF promote cancer progression through pleiotropic mechanisms, including the secretion of soluble factors and extracellular matrix, physical interactions with cancer cells, and the regulation of angiogenesis, immunity and metabolism. Their contribution to therapeutic resistance is also well appreciated. Therefore, CAF have been considered as a therapeutic target in cancer. However, recent studies in autochthonous pancreatic cancer models suggest that specific subset(s) of CAF exhibit cancer-restraining roles, indicating that CAF are functionally and molecularly heterogeneous, which is supported by recent single-cell transcriptome analyses. While cancer-promoting CAF (pCAF) have been extensively studied, the nature and specific marker(s) of cancer-restraining CAF (rCAF) have remained uncharacterized. Interestingly, a recent study provided insight into the nature of rCAF and suggested that they may share molecular properties with pancreatic stellate cells (PSC) and mesenchymal stem/stromal cells (MSC). Complicating this finding is that PSC and MSC have been shown to promote the formation of a tumor-permissive and tumor-promoting environment in xenograft tumor models. However, these cells undergo significant transcriptional and epigenetic changes during ex vivo culture, which confounds the interpretation of experimental results based on the use of cultured cells. In this short review, we describe recent studies and hypotheses on the identity of rCAF and discuss their analogy to fibroblasts that suppress fibrosis in fibrotic diseases. Finally, we discuss how these findings can be exploited to develop novel anticancer therapies in the future.
癌症相关成纤维细胞（CAF）在各种类型癌症的进展中的作用已得到充分证实。CAF 通过多种机制促进癌症进展，包括分泌可溶性因子和细胞外基质、与癌细胞的物理相互作用、以及调节血管生成、免疫和代谢。它们对治疗耐药性的贡献也得到了充分的认识。因此，CAF 已被认为是癌症的治疗靶点。然而，最近在自发胰腺癌模型中的研究表明，特定的 CAF 亚群表现出抑制癌症的作用，这表明 CAF 在功能和分子上是异质的，这得到了最近的单细胞转录组分析的支持。虽然促癌 CAF（pCAF）已被广泛研究，但抑制癌 CAF（rCAF）的性质和特定标志物仍未被确定。有趣的是，最近的一项研究深入了解了 rCAF 的性质，并表明它们可能与胰腺星状细胞（PSC）和间充质干细胞/基质细胞（MSC）具有共同的分子特性。使这一发现复杂化的是，PSC 和 MSC 已被证明在异种移植肿瘤模型中促进了肿瘤允许和促进肿瘤生长的环境的形成。然而，这些细胞在体外培养过程中经历了显著的转录和表观遗传变化，这使得基于使用培养细胞的实验结果的解释变得复杂。在这篇简短的综述中，我们描述了 rCAF 的身份的最新研究和假设，并讨论了它们与抑制纤维化疾病中纤维化的成纤维细胞的类似性。最后，我们讨论了如何利用这些发现来开发未来的新型抗癌疗法。
