High CD142 Level Marks Tumor-Promoting Fibroblasts with Targeting Potential in Colorectal Cancer

Soós, András Áron and Kelemen, Andrea and Orosz, Adrián and Szvicsek, Zsuzsanna and Tölgyes, Tamás and Dede, Kristóf and Bursics, Attila and Wiener, Zoltán (2023) High CD142 Level Marks Tumor-Promoting Fibroblasts with Targeting Potential in Colorectal Cancer. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 24 (14). No. 11585. ISSN 1661-6596

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Colorectal cancer (CRC) has a high incidence and is one of the leading causes of cancer-related death. The accumulation of cancer-associated fibroblasts (CAF) induces an aggressive, stem-like phenotype in tumor cells, and it indicates a poor prognosis. However, cellular heterogeneity among CAFs and the targeting of both stromal and CRC cells are not yet well resolved. Here, we identified CD142high fibroblasts with a higher stimulating effect on CRC cell proliferation via secreting more hepatocyte growth factor (HGF) compared to CD142low CAFs. We also found that combinations of inhibitors that had either a promising effect in other cancer types or are more active in CRC compared to normal colonic epithelium acted synergistically in CRC cells. Importantly, heat shock protein 90 (HSP90) inhibitor selected against CD142high fibroblasts, and both CRC cells and CAFs were sensitive to a BCL-xL inhibitor. However, targeting mitogen-activated protein kinase kinase (MEK) was ineffective in fibroblasts, and an epigenetic inhibitor selected for a tumor cell population with markers of aggressive behavior. Thus, we suggest BCL-xL and HSP90 inhibitors to eliminate cancer cells and decrease the tumor-promoting CD142high CAF population. This may be the basis of a strategy to target both CRC cells and stromal fibroblasts, resulting in the inhibition of tumor relapse.

Item Type: Article
Uncontrolled Keywords: colorectal cancer; cancer-associated fibroblast; CAF; organoid; drug sensitivity; heterogeneity; inhibitor; BCL family; hepatocyte growth factor; HGF; tissue factor; F3; HSP90; JQ1; MEK
Subjects: R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia
Depositing User: Dr Zoltán Wiener
Date Deposited: 07 Sep 2023 11:50
Last Modified: 07 Sep 2023 11:50

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