Cancer-associated mesothelial cells promote ovarian cancer chemoresistance through paracrine osteopontin signaling

Qian, Jin; LeSavage, Bauer L.; Hubka, Kelsea M.; Ma, Chenkai; Natarajan, Suchitra; Eggold, Joshua T.; Xiao, Yiren; Fuh, Katherine C.; Krishnan, Venkatesh; Enejder, Annika; Heilshorn, Sarah C.; Dorigo, Oliver; Rankin, Erinn B.

doi:10.1172/jci146186

Cited by 65 publications

(32 citation statements)

References 90 publications

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“…37 Now, SPP1 has been found to abnormally express in a variety of cancers, and induces drug resistance, progression, recurrence, and metastasis in breast, ovarian, and colon cancer. [38][39][40] However, related resistance genes could be identified in both resistant cell lines and wild-type cells. Similarly, some kinds of TP53 mutation could be in found in NSCLC with or without EGFR mutation.…”

Section: Discussionmentioning

confidence: 99%

The Multi-Omics Analysis of Key Genes Regulating EGFR-TKI Resistance, Immune Infiltration, SCLC Transformation in EGFR-Mutant NSCLC

Wang¹,

Zhang²,

Xu³

et al. 2022

JIR

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Background: Lung cancer is a high-risk malignancy worldwide. The harboring of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) makes EGFR-tyrosine kinase inhibitor (EGFR-TKI) an attractive therapeutic option. However, patients usually suffer the primary and secondary resistance to EGFR-TKI. And the molecular alteration is still not fully clear and needs further study. Methods: The GEO database was utilized to find the differentially expressed genes (DEGs) in NSCLC profiles resistant to the 1st or 2nd generation EGFR-TKI. We analyzed the expression and pathway enrichment of hub genes, and the prognosis of EGFR mutant/ wild-type lung adenocarcinoma (LUAD). Moreover, small cell lung cancer (SCLC) and TKI-resistant profiles were used to find common DEGs, and construct miRNA regulatory network. Analysis was performed of hub genes' related immune infiltration, drug sensitivity, and methylation. Further, we analyzed hub gene expression in EGFR-mutant LUAD and paracancerous tissue by qRT-PCR. Results: A total of 107 DEGs were found related to TKI resistance. Eleven hub genes were obtained after visualization, of which 5 hub genes were co-expressed in SCLC with common miRNAs. Lower expression of SPP1 (hub gene) was associated with better survival in NSCLC. The immune infiltration analysis showed more CD4+ T cells in the resistant group with high expression of SPP1. SPP1 and CD44 promoters' methylations were independent prognostic factors of LUAD. And the expression level of SPP1 related to the sensitivity of EGFR-TKIs in multiple cancer cell lines. qRT-PCR validated the higher expression of SPP1 in EGFR-mutant LUAD than in normal tissue. Conclusion:Our study suggested that the upregulation of SPP1 might induce resistance to the 1st and 2nd generation EGFR-TKI, and influence tumor immune infiltration, resulting in poor survival. ZEB1, SPP1, MUC1, CD44, and ESRP1 might be molecular drivers of SCLC transformation of TKI resistance.

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Section: Discussionmentioning

confidence: 99%

The Multi-Omics Analysis of Key Genes Regulating EGFR-TKI Resistance, Immune Infiltration, SCLC Transformation in EGFR-Mutant NSCLC

Wang¹,

Zhang²,

Xu³

et al. 2022

JIR

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“…In turn, osteopontin facilitated ovarian cancer cell chemoresistance via activation of the CD44 receptor, PI3K/AKT signaling, and ABC drug efflux transporter activity. 80 By contrast, MCs have been reported to be a source of apCAFs. Because MCs possess antigen-presenting 26 ASPN, asporin; CAF, cancer-associated fibroblast; NF, normal fibroblast; ROS, reactive oxygen species function in peritoneal immunity, MC-CAFs may also contribute to such anti-tumor immunity in some situations.…”

Section: Roles Of Mc-derived Cafs (Mc-cafs) In Cancer Progression Mc-...mentioning

confidence: 98%

“…Ovarian cancer cells were found to induce osteopontin expression and secretion by MCs through TGF‐β signaling. In turn, osteopontin facilitated ovarian cancer cell chemoresistance via activation of the CD44 receptor, PI3K/AKT signaling, and ABC drug efflux transporter activity 80 . By contrast, MCs have been reported to be a source of apCAFs.…”

Section: Roles Of Mc‐derived Cafs (Mc‐cafs) In Cancer Progressionmentioning

confidence: 99%

Crosstalk of tumor stromal cells orchestrates invasion and spreading of gastric cancer

Tanaka

2022

Pathology International

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Tumors contain various stromal cells that support cancer progression. Some types of cancer, such as scirrhous gastric cancer, are characterized by large areas of fibrosis accompanied by cancer‐associated fibroblasts (CAFs). Asporin (ASPN) is a small leucine‐rich proteoglycan highly expressed in CAFs of various tumors. ASPN accelerates CAF migration and invasion, resulting in CAF‐led cancer cell invasion. In addition, ASPN further upregulated the expression of genes specific to a characteristic subgroup of fibroblasts in tumors. These cells were preferentially located at the tumor periphery and could be generated by a unique mechanism involving the CAF‐mediated education of normal fibroblasts (CEFs). In this review, we at first describe recent findings regarding the function of ASPN in the tumor microenvironment, as well as the mechanism involved in the generation of CEFs. CAFs are derived from heterogeneous origins besides resident normal fibroblasts. Among them, CAFs derived from mesothelial cells (mesothelial cell‐derived CAF [MC‐CAFs]) play pivotal roles in peritoneal carcinomatosis. We observed that MC‐CAFs on the surfaces of organs also participate in tumor formation by infiltrating into the parenchyma, promoting local invasion by gastric cancers. This review also highlights the potential functions of macrophages in the formation of MC‐CAFs in gastric cancers, by transfer the contents of cancer cell‐derived extracellular vesicles.

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“…Osteopontin (OPN) is a glycoprotein released by mesothelial cells under the influence of TGF-ß and potentiates chemoresistance in ovarian cancer cells. It signals through the binding of CD44 and integrins on cancer cells and activates PI3k/AKT tumor survival pathway and the expression of ATP-binding cassette (ABC) transporters involved in drug efflux, a similar mechanism to the upregulation of copper transporters ATP7A and ATP7B that function to efflux platinum from the cell leading to chemoresistance ( 190 , 191 ). Another study showed that the upregulation of fibronectin on the surface of mesothelial cells, induced by TGF-ß, caused chemoresistance in ovarian cancer cells via the PI3K/AKT pathway ( 119 ).…”

Section: Microenvironment and Chemoresistancementioning

confidence: 99%

The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination

Ritch

Telleria

2022

Front. Endocrinol.

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Epithelial ovarian cancer (EOC) is considered the deadliest gynecological disease and is normally diagnosed at late stages, at which point metastasis has already occurred. Throughout disease progression, EOC will encounter various ecosystems and the communication between cancer cells and these microenvironments will promote the survival and dissemination of EOC. The primary tumor is thought to develop within the ovaries or the fallopian tubes, both of which provide a microenvironment with high risk of causing DNA damage and enhanced proliferation. EOC disseminates by direct extension from the primary tumors, as single cells or multicellular aggregates. Under the influence of cellular and non-cellular factors, EOC spheroids use the natural flow of peritoneal fluid to reach distant organs within the peritoneal cavity. These cells can then implant and seed distant organs or tissues, which develop rapidly into secondary tumor nodules. The peritoneal tissue and the omentum are two common sites of EOC metastasis, providing a microenvironment that supports EOC invasion and survival. Current treatment for EOC involves debulking surgery followed by platinum-taxane combination chemotherapy; however, most patients will relapse with a chemoresistant disease with tumors developed within the peritoneum. Therefore, understanding the role of the unique microenvironments that promote EOC transcoelomic dissemination is important in improving patient outcomes from this disease. In this review article, we address the process of ovarian cancer cellular fate at the site of its origin in the secretory cells of the fallopian tube or in the ovarian surface epithelial cells, their detachment process, how the cells survive in the peritoneal fluid avoiding cell death triggers, and how cancer- associated cells help them in the process. Finally, we report the mechanisms used by the ovarian cancer cells to adhere and migrate through the mesothelial monolayer lining the peritoneum. We also discuss the involvement of the transcoelomic ecosystem on the development of chemoresistance of EOC.

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Cancer-associated mesothelial cells promote ovarian cancer chemoresistance through paracrine osteopontin signaling

Abstract: izing Abs may enhance the efficacy of chemotherapy in the clinical management of ovarian cancer and other abdominal cancers with peritoneal metastases warrants further investigation (88, 89).

Cited by 65 publications

References 90 publications

The Multi-Omics Analysis of Key Genes Regulating EGFR-TKI Resistance, Immune Infiltration, SCLC Transformation in EGFR-Mutant NSCLC

The Multi-Omics Analysis of Key Genes Regulating EGFR-TKI Resistance, Immune Infiltration, SCLC Transformation in EGFR-Mutant NSCLC

Crosstalk of tumor stromal cells orchestrates invasion and spreading of gastric cancer

The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination

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