Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Cells. 2022 Nov 25;11(23):3769. doi: 10.3390/cells11233769.
Cancer-associated fibroblasts (CAFs) and their extracellular matrix are active participants in cancer progression. While it is known that functionally different subpopulations of CAFs co-exist in ovarian cancer, it is unclear whether certain CAF subsets are enriched during metastatic progression and/or chemotherapy. Using computational image analyses of patient-matched primary high-grade serous ovarian carcinomas, synchronous pre-chemotherapy metastases, and metachronous post-chemotherapy metastases from 42 patients, we documented the dynamic spatiotemporal changes in the extracellular matrix, fibroblasts, epithelial cells, immune cells, and CAF subsets expressing different extracellular matrix components. Among the different CAF subsets, COL11A1 CAFs were associated with linearized collagen fibers and exhibited the greatest enrichment in pre- and post-chemotherapy metastases compared to matched primary tumors. Although pre- and post-chemotherapy metastases were associated with increased CD8 T cell infiltration, the infiltrate was not always evenly distributed between the stroma and cancer cells, leading to an increased frequency of the immune-excluded phenotype where the majority of CD8 T cells are present in the tumor stroma but absent from the tumor parenchyma. Overall, most of the differences in the tumor microenvironment were observed between primary tumors and metastases, while fewer differences were observed between pre- and post-treatment metastases. These data suggest that the tumor microenvironment is largely determined by the primary vs. metastatic location of the tumor while chemotherapy does not have a significant impact on the host microenvironment.
癌症相关成纤维细胞（CAFs）及其细胞外基质是癌症进展的积极参与者。虽然已知在卵巢癌中存在功能不同的 CAF 亚群，但尚不清楚在转移进展和/或化疗过程中是否会富集某些 CAF 亚群。我们通过对 42 名患者的配对原发性高级别浆液性卵巢癌、同步化疗前转移灶和化疗后同期转移灶进行计算图像分析，记录了细胞外基质、成纤维细胞、上皮细胞、免疫细胞以及表达不同细胞外基质成分的 CAF 亚群的动态时空变化。在不同的 CAF 亚群中，COL11A1 CAFs 与线性化胶原纤维相关，并且与配对原发性肿瘤相比，在化疗前和化疗后转移灶中富集程度最高。尽管化疗前和化疗后转移灶与 CD8 T 细胞浸润增加相关，但浸润并不总是在基质和癌细胞之间均匀分布，导致免疫排斥表型的频率增加，即大多数 CD8 T 细胞存在于肿瘤基质中而不存在于肿瘤实质中。总体而言，肿瘤微环境的大多数差异发生在原发性肿瘤和转移灶之间，而在化疗前和化疗后转移灶之间观察到的差异较少。这些数据表明，肿瘤微环境主要由肿瘤的原发性与转移性位置决定，而化疗对宿主微环境没有显著影响。
