The interplay of cancer-associated fibroblasts and apoptotic cancer cells suppresses lung cancer cell growth through WISP-1-integrin ανβ3-STAT1 signaling pathway
Abstract Background Cell death within the tumor microenvironment (TME) plays a crucial role in controlling cancer by influencing the balance of tumor-specific immunity. Cancer-associated fibroblasts (CAFs) significantly contribute to tumor progression through paracrine mechanisms. We found that repr...
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BMC
2025-02-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02094-2 |
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| author | Shinyoung Kim Kyungwon Yang Kiyoon Kim Hee Ja Kim Da Young Kim Jeesoo Chae Young-Ho Ahn Jihee Lee Kang |
| author_facet | Shinyoung Kim Kyungwon Yang Kiyoon Kim Hee Ja Kim Da Young Kim Jeesoo Chae Young-Ho Ahn Jihee Lee Kang |
| author_sort | Shinyoung Kim |
| collection | DOAJ |
| description | Abstract Background Cell death within the tumor microenvironment (TME) plays a crucial role in controlling cancer by influencing the balance of tumor-specific immunity. Cancer-associated fibroblasts (CAFs) significantly contribute to tumor progression through paracrine mechanisms. We found that reprogramming of CAFs by apoptotic cancer cells suppresses tumor volume and lung metastasis. Here, we investigated the mechanisms by which the interaction between apoptotic lung cancer cells and CAFs hinders tumor growth. Methods Experimental methods including CCK assay, colony formation assay, immunoblotting, co-immunoprecipitation, qRT-PCR analysis, qRT-PCR array, apoptosis assay, ELISA, and immunofluorescent staining were used in this study. Additionally, CAFs were isolated from lung tumors of Kras-mutant (KrasLA1) mice and human lung adenocarcinoma samples using magnetic-activated cell sorting. Murine lung cancer cells (344SQ cells) along with various human cancer cell lines (A549, HCT116, and LoVo) were cultured. In animal study, conditioned medium (CM) derived from CAFs (undiluted or 50% diluted) with or without neutralizing anti-WISP-1 antibody was administered into syngeneic mice to study anti-tumoral effects. To confirm the paracrine role of WISP-1, recombinant WISP-1 (rWISP-1) was administered via intratumoral injection. Results We demonstrate that treatment with CM from lung CAFs exposed to apoptotic cancer cells suppresses proliferation and promotes apoptosis in lung cancer cells through STAT1 signaling. Pharmacologic inhibition of Notch1 activation or siRNA-mediated Notch1 silencing in CAFs reversed the antiproliferative and proapoptotic effects. Similarly, knockdown of Wnt-induced signaling protein 1 (WISP-1) in CAFs or neutralizing the CM with anti-WISP-1 antibodies reversed the antiproliferative and proapoptotic effects. WISP-1 signaled through integrin ανβ3-STAT1 signaling pathway to inhibit cancer cell growth and promote apoptosis. The in vivo introduction of CM derived from apoptotic 344SQ-exposed CAFs (ApoSQ-CAF CM) potently decelerated tumor growth. This effect was observed alongside the downregulation of proliferative and anti-apoptotic markers, while simultaneously boosting the activation of phosphorylated STAT1 and pro-apoptotic markers in CD326+ tumor cells within syngeneic immunocompetent mice. rWISP-1 effectively replicates the in vivo effects of ApoSQ-CAF CM. Conclusions These findings suggest that CM from apoptotic cancer cell-exposed CAFs may offer a promising therapeutic approach by lung cancer suppression. |
| format | Article |
| id | doaj-art-e65c8ede8cd148a1b7ef2dce71b37785 |
| institution | DOAJ |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-e65c8ede8cd148a1b7ef2dce71b377852025-08-20T03:13:15ZengBMCCell Communication and Signaling1478-811X2025-02-0123112410.1186/s12964-025-02094-2The interplay of cancer-associated fibroblasts and apoptotic cancer cells suppresses lung cancer cell growth through WISP-1-integrin ανβ3-STAT1 signaling pathwayShinyoung Kim0Kyungwon Yang1Kiyoon Kim2Hee Ja Kim3Da Young Kim4Jeesoo Chae5Young-Ho Ahn6Jihee Lee Kang7Department of Physiology, College of Medicine, Ewha Womans UniversityDepartment of Physiology, College of Medicine, Ewha Womans UniversityInflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans UniversityDepartment of Physiology, College of Medicine, Ewha Womans UniversityDepartment of Physiology, College of Medicine, Ewha Womans UniversityDepartment of Biochemistry, College of Medicine, Ewha Womans UniversityInflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans UniversityDepartment of Physiology, College of Medicine, Ewha Womans UniversityAbstract Background Cell death within the tumor microenvironment (TME) plays a crucial role in controlling cancer by influencing the balance of tumor-specific immunity. Cancer-associated fibroblasts (CAFs) significantly contribute to tumor progression through paracrine mechanisms. We found that reprogramming of CAFs by apoptotic cancer cells suppresses tumor volume and lung metastasis. Here, we investigated the mechanisms by which the interaction between apoptotic lung cancer cells and CAFs hinders tumor growth. Methods Experimental methods including CCK assay, colony formation assay, immunoblotting, co-immunoprecipitation, qRT-PCR analysis, qRT-PCR array, apoptosis assay, ELISA, and immunofluorescent staining were used in this study. Additionally, CAFs were isolated from lung tumors of Kras-mutant (KrasLA1) mice and human lung adenocarcinoma samples using magnetic-activated cell sorting. Murine lung cancer cells (344SQ cells) along with various human cancer cell lines (A549, HCT116, and LoVo) were cultured. In animal study, conditioned medium (CM) derived from CAFs (undiluted or 50% diluted) with or without neutralizing anti-WISP-1 antibody was administered into syngeneic mice to study anti-tumoral effects. To confirm the paracrine role of WISP-1, recombinant WISP-1 (rWISP-1) was administered via intratumoral injection. Results We demonstrate that treatment with CM from lung CAFs exposed to apoptotic cancer cells suppresses proliferation and promotes apoptosis in lung cancer cells through STAT1 signaling. Pharmacologic inhibition of Notch1 activation or siRNA-mediated Notch1 silencing in CAFs reversed the antiproliferative and proapoptotic effects. Similarly, knockdown of Wnt-induced signaling protein 1 (WISP-1) in CAFs or neutralizing the CM with anti-WISP-1 antibodies reversed the antiproliferative and proapoptotic effects. WISP-1 signaled through integrin ανβ3-STAT1 signaling pathway to inhibit cancer cell growth and promote apoptosis. The in vivo introduction of CM derived from apoptotic 344SQ-exposed CAFs (ApoSQ-CAF CM) potently decelerated tumor growth. This effect was observed alongside the downregulation of proliferative and anti-apoptotic markers, while simultaneously boosting the activation of phosphorylated STAT1 and pro-apoptotic markers in CD326+ tumor cells within syngeneic immunocompetent mice. rWISP-1 effectively replicates the in vivo effects of ApoSQ-CAF CM. Conclusions These findings suggest that CM from apoptotic cancer cell-exposed CAFs may offer a promising therapeutic approach by lung cancer suppression.https://doi.org/10.1186/s12964-025-02094-2CAFApoptotic cancer cellLung cancerWISP-1-integrin ανβ3-STAT1 signaling pathwayTumor growth |
| spellingShingle | Shinyoung Kim Kyungwon Yang Kiyoon Kim Hee Ja Kim Da Young Kim Jeesoo Chae Young-Ho Ahn Jihee Lee Kang The interplay of cancer-associated fibroblasts and apoptotic cancer cells suppresses lung cancer cell growth through WISP-1-integrin ανβ3-STAT1 signaling pathway Cell Communication and Signaling CAF Apoptotic cancer cell Lung cancer WISP-1-integrin ανβ3-STAT1 signaling pathway Tumor growth |
| title | The interplay of cancer-associated fibroblasts and apoptotic cancer cells suppresses lung cancer cell growth through WISP-1-integrin ανβ3-STAT1 signaling pathway |
| title_full | The interplay of cancer-associated fibroblasts and apoptotic cancer cells suppresses lung cancer cell growth through WISP-1-integrin ανβ3-STAT1 signaling pathway |
| title_fullStr | The interplay of cancer-associated fibroblasts and apoptotic cancer cells suppresses lung cancer cell growth through WISP-1-integrin ανβ3-STAT1 signaling pathway |
| title_full_unstemmed | The interplay of cancer-associated fibroblasts and apoptotic cancer cells suppresses lung cancer cell growth through WISP-1-integrin ανβ3-STAT1 signaling pathway |
| title_short | The interplay of cancer-associated fibroblasts and apoptotic cancer cells suppresses lung cancer cell growth through WISP-1-integrin ανβ3-STAT1 signaling pathway |
| title_sort | interplay of cancer associated fibroblasts and apoptotic cancer cells suppresses lung cancer cell growth through wisp 1 integrin ανβ3 stat1 signaling pathway |
| topic | CAF Apoptotic cancer cell Lung cancer WISP-1-integrin ανβ3-STAT1 signaling pathway Tumor growth |
| url | https://doi.org/10.1186/s12964-025-02094-2 |
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