Cancer-associated fibroblast-derived PAI-1 promotes lymphatic metastasis via the induction of EndoMT in lymphatic endothelial cells
Abstract Background Endothelial-mesenchymal transition (EndoMT) is an emerging adaptive process that modulates lymphatic endothelial function to drive aberrant lymphatic vascularization in the tumour microenvironment (TME); however, the molecular determinants that govern the functional role of EndoM...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-023-02714-0 |
| _version_ | 1827905220164714496 |
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| author | Wen-Fei Wei Hui-Ling Zhou Pei-Yu Chen Xiao-Lan Huang Long Huang Luo-Jiao Liang Chu-Hong Guo Chen-Fei Zhou Lan Yu Liang-Sheng Fan Wei Wang |
| author_facet | Wen-Fei Wei Hui-Ling Zhou Pei-Yu Chen Xiao-Lan Huang Long Huang Luo-Jiao Liang Chu-Hong Guo Chen-Fei Zhou Lan Yu Liang-Sheng Fan Wei Wang |
| author_sort | Wen-Fei Wei |
| collection | DOAJ |
| description | Abstract Background Endothelial-mesenchymal transition (EndoMT) is an emerging adaptive process that modulates lymphatic endothelial function to drive aberrant lymphatic vascularization in the tumour microenvironment (TME); however, the molecular determinants that govern the functional role of EndoMT remain unclear. Here, we show that cancer-associated fibroblast (CAF)-derived PAI-1 promoted the EndoMT of lymphatic endothelial cells (LECs) in cervical squamous cell carcinoma (CSCC). Methods Immunofluorescent staining of α-SMA, LYVE-1 and DAPI were examined in primary tumour samples obtained from 57 CSCC patients. Assessment of cytokines secreted by CAFs and normal fibroblasts (NFs) was performed using human cytokine antibody arrays. The phenotype of EndoMT in lymphatic endothelial cells (LECs), gene expression levels, protein secretion and activity of signaling pathways were measured by real-time RT-PCR, ELISA or western blotting. The function of lymphatic endothelial monolayers was examined by transwell, tube formation assay, transendothelial migration assay in vitro. Lymphatic metastasis was measured using popliteal lymph node metastasis model. Furthermore, association between PAI-1 expression and EndoMT in CSCC was analyzed by immunohistochemistry. The Cancer Genome Atlas (TCGA) databases was used to assess the association of PAI-1 with survival rate in CSCC. Results CAF-derived PAI-1 promoted the EndoMT of LECs in CSCC. LECs undergoing EndoMT could initiate tumour neolymphangiogenesis that facilitated cancer cell intravasation/extravasation, which in turn promoted lymphatic metastasis in CSCC. Mechanistically, PAI-1 activated the AKT/ERK1/2 pathways by directly interacting with low-density lipoprotein receptor-related protein (LRP1), thereby leading to elevated EndoMT activity in LECs. Blockade of PAI-1 or inhibition of LRP1/AKT/ERK1/2 abrogated EndoMT and consequently attenuated CAF-induced tumour neolymphangiogenesis. Furthermore, clinical data revealed that increased PAI-1 levels positively correlated with EndoMT activity and poor prognosis in CSCC patients. Conclusion Our data indicate that CAF-derived PAI-1 acts as an important neolymphangiogenesis-initiating molecular during CSCC progression through modulating the EndoMT of LECs, resulting in promotion of metastasis ability in primary site. PAI-1 could serve as an effective prognostic biomarker and therapeutic target for CSCC metastasis. |
| first_indexed | 2024-03-13T00:38:54Z |
| format | Article |
| id | doaj.art-97e16b1b4a6842f3a20df3116fc27883 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-03-13T00:38:54Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-97e16b1b4a6842f3a20df3116fc278832023-07-09T11:28:06ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-07-0142111510.1186/s13046-023-02714-0Cancer-associated fibroblast-derived PAI-1 promotes lymphatic metastasis via the induction of EndoMT in lymphatic endothelial cellsWen-Fei Wei0Hui-Ling Zhou1Pei-Yu Chen2Xiao-Lan Huang3Long Huang4Luo-Jiao Liang5Chu-Hong Guo6Chen-Fei Zhou7Lan Yu8Liang-Sheng Fan9Wei Wang10Department of Gynaecology, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated With Jinan University)Department of Obstetrics and Gynaecology, Nanfang Hospital, Southern Medical UniversityDepartment of Obstetrics and Gynaecology, Nanfang Hospital, Southern Medical UniversityDepartment of Obstetrics and Gynaecology, Nanfang Hospital, Southern Medical UniversityDepartment of Urology, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated With Jinan University)Department of Obstetrics and Gynaecology, Nanfang Hospital, Southern Medical UniversityDepartment of Obstetrics and Gynaecology, Nanfang Hospital, Southern Medical UniversityDepartment of Gynecology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical SciencesDepartment of Gynecologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterDepartment of Obstetrics and Gynaecology, Nanfang Hospital, Southern Medical UniversityDepartment of Gynaecology, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated With Jinan University)Abstract Background Endothelial-mesenchymal transition (EndoMT) is an emerging adaptive process that modulates lymphatic endothelial function to drive aberrant lymphatic vascularization in the tumour microenvironment (TME); however, the molecular determinants that govern the functional role of EndoMT remain unclear. Here, we show that cancer-associated fibroblast (CAF)-derived PAI-1 promoted the EndoMT of lymphatic endothelial cells (LECs) in cervical squamous cell carcinoma (CSCC). Methods Immunofluorescent staining of α-SMA, LYVE-1 and DAPI were examined in primary tumour samples obtained from 57 CSCC patients. Assessment of cytokines secreted by CAFs and normal fibroblasts (NFs) was performed using human cytokine antibody arrays. The phenotype of EndoMT in lymphatic endothelial cells (LECs), gene expression levels, protein secretion and activity of signaling pathways were measured by real-time RT-PCR, ELISA or western blotting. The function of lymphatic endothelial monolayers was examined by transwell, tube formation assay, transendothelial migration assay in vitro. Lymphatic metastasis was measured using popliteal lymph node metastasis model. Furthermore, association between PAI-1 expression and EndoMT in CSCC was analyzed by immunohistochemistry. The Cancer Genome Atlas (TCGA) databases was used to assess the association of PAI-1 with survival rate in CSCC. Results CAF-derived PAI-1 promoted the EndoMT of LECs in CSCC. LECs undergoing EndoMT could initiate tumour neolymphangiogenesis that facilitated cancer cell intravasation/extravasation, which in turn promoted lymphatic metastasis in CSCC. Mechanistically, PAI-1 activated the AKT/ERK1/2 pathways by directly interacting with low-density lipoprotein receptor-related protein (LRP1), thereby leading to elevated EndoMT activity in LECs. Blockade of PAI-1 or inhibition of LRP1/AKT/ERK1/2 abrogated EndoMT and consequently attenuated CAF-induced tumour neolymphangiogenesis. Furthermore, clinical data revealed that increased PAI-1 levels positively correlated with EndoMT activity and poor prognosis in CSCC patients. Conclusion Our data indicate that CAF-derived PAI-1 acts as an important neolymphangiogenesis-initiating molecular during CSCC progression through modulating the EndoMT of LECs, resulting in promotion of metastasis ability in primary site. PAI-1 could serve as an effective prognostic biomarker and therapeutic target for CSCC metastasis.https://doi.org/10.1186/s13046-023-02714-0Cancer-associated fibroblastEndothelial-mesenchymal transitionCervical squamous cell carcinomaLymphatic metastasisPAI-1 |
| spellingShingle | Wen-Fei Wei Hui-Ling Zhou Pei-Yu Chen Xiao-Lan Huang Long Huang Luo-Jiao Liang Chu-Hong Guo Chen-Fei Zhou Lan Yu Liang-Sheng Fan Wei Wang Cancer-associated fibroblast-derived PAI-1 promotes lymphatic metastasis via the induction of EndoMT in lymphatic endothelial cells Journal of Experimental & Clinical Cancer Research Cancer-associated fibroblast Endothelial-mesenchymal transition Cervical squamous cell carcinoma Lymphatic metastasis PAI-1 |
| title | Cancer-associated fibroblast-derived PAI-1 promotes lymphatic metastasis via the induction of EndoMT in lymphatic endothelial cells |
| title_full | Cancer-associated fibroblast-derived PAI-1 promotes lymphatic metastasis via the induction of EndoMT in lymphatic endothelial cells |
| title_fullStr | Cancer-associated fibroblast-derived PAI-1 promotes lymphatic metastasis via the induction of EndoMT in lymphatic endothelial cells |
| title_full_unstemmed | Cancer-associated fibroblast-derived PAI-1 promotes lymphatic metastasis via the induction of EndoMT in lymphatic endothelial cells |
| title_short | Cancer-associated fibroblast-derived PAI-1 promotes lymphatic metastasis via the induction of EndoMT in lymphatic endothelial cells |
| title_sort | cancer associated fibroblast derived pai 1 promotes lymphatic metastasis via the induction of endomt in lymphatic endothelial cells |
| topic | Cancer-associated fibroblast Endothelial-mesenchymal transition Cervical squamous cell carcinoma Lymphatic metastasis PAI-1 |
| url | https://doi.org/10.1186/s13046-023-02714-0 |
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