小柯机器人

近日，德国法兰克福大学Florian R. Greten及其团队发现，炎性成纤维细胞介导对直肠癌新辅助治疗的抵抗。这一研究成果于2022年2月3日在线发表在国际学术期刊《癌细胞》上。

在直肠癌患者中，研究人员发现炎症性癌症相关的成纤维细胞（iCAF）与化疗反应不佳有关。通过采用小鼠直肠癌模型或患者衍生的肿瘤类器官和原生基质细胞，结果表明，在辐照后，白细胞介素-1α（IL-1α）不仅使癌症相关成纤维细胞向炎症表型分化，而且还引发氧化性DNA损伤，从而使iCAF易受p53介导治疗引起的衰老，这反过来又导致了化放疗的阻力和疾病进展。一致的是，抑制IL-1、防止iCAF衰老或衰老疗法使小鼠对辐照敏感，而直肠癌患者较低的IL-1受体拮抗剂血清水平与不良预后相关。

总之，研究人员揭示了iCAF在直肠癌治疗抗性中的关键作用，并确定IL-1信号是一个有吸引力的靶点，可以使基质复极化和预防癌症相关的成纤维细胞衰老。

据介绍，标准的癌症治疗以肿瘤细胞为目标，而不考虑肿瘤微环境可能受到的损害，从而影响治疗反应。

附：英文原文

Title: Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

Author: Adele M. Nicolas, Marina Pesic, Esther Engel, Paul K. Ziegler, Markus Diefenhardt, Kilian B. Kennel, Florian Buettner, Claire Conche, Valentina Petrocelli, Eiman Elwakeel, Andreas Weigert, Anna Zinoveva, Maximilian Fleischmann, Bjrn Hupl, Cem Karakütük, Hanibal Bohnenberger, Mohammed H. Mosa, Lars Kaderali, Jochen Gaedcke, Michael Ghadimi, Franz Rdel, Melek C. Arkan, Thomas Oellerich, Claus Rdel, Emmanouil Fokas, Florian R. Greten

Issue&Volume: 2022-02-03

Abstract: Standard cancer therapy targets tumor cells without considering possible damage on the tumor microenvironment that could impair therapy response. In rectal cancer patients we find that inflammatory cancer-associated fibroblasts (iCAFs) are associated with poor chemoradiotherapy response. Employing a murine rectal cancer model or patient-derived tumor organoids and primary stroma cells, we show that, upon irradiation, interleukin-1α (IL-1α) not only polarizes cancer-associated fibroblasts toward the inflammatory phenotype but also triggers oxidative DNA damage, thereby predisposing iCAFs to p53-mediated therapy-induced senescence, which in turn results in chemoradiotherapy resistance and disease progression. Consistently, IL-1 inhibition, prevention of iCAFs senescence, or senolytic therapy sensitizes mice to irradiation, while lower IL-1 receptor antagonist serum levels in rectal patients correlate with poor prognosis. Collectively, we unravel a critical role for iCAFs in rectal cancer therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of cancer-associated fibroblasts senescence.

DOI: 10.1016/j.ccell.2022.01.004

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00006-X

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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