Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion

Kenny, Hilary A.; Chiang, Ching-Yu; White, Erin A.; Schryver, Elizabeth M.; Habis, Mohammed; Romero, Iris L.; Ladányi, András; Penicka, Carla; George, Joshy; Matlin, Karl S.; Montag, Anthony; Wroblewski, Kristen; Yamada, S. Diane; Mazar, Andrew P.; Bowtell, David D.L.; Lengyel, Ernst

doi:10.1172/jci74778

Cited by 258 publications

(322 citation statements)

References 62 publications

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“…These findings indicate reciprocal interactions between both cell types mediated by secreted factors. Further investigations have implicated fibronectin in formation and adhesion to peritoneal cells of OvCa spheroids (77,78). These observations are compatible with earlier findings of detection of covalently-linked fibrinfibronectin compounds in the stroma surrounding ovarian cancer metastases and in corresponding ascites (79).…”

Section: Possible Targets For Therapeutic Interventionsupporting

confidence: 88%

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Mechanisms and Targets Involved in Dissemination of Ovarian Cancer

Weidle

Birzele

Kollmorgen

et al. 2016

CGP

112

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Section: Possible Targets For Therapeutic Interventionsupporting

confidence: 88%

“…Mesothelial cell-secreted fibronectin was identified and investigated in more detail (78). It was shown that human mesothelial cells secrete fibronectin in the presence of OvCa cells in organotypic 3D cultures and that fibronectin was consistently overexpressed in the stroma of 108 omental metastases.…”

Section: Possible Targets For Therapeutic Interventionmentioning

confidence: 99%

Mechanisms and Targets Involved in Dissemination of Ovarian Cancer

Weidle

Birzele

Kollmorgen

et al. 2016

CGP

112

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“…In addition, the primary cells are always used at an early (1-2) passage to preserve morphology. Mesothelial cells can be cuboidal or spindly, and cuboidal mesothelial cells become more spindly as they are passaged, or with greater exposure to conditioned media from ovarian cancer cells or treatment with TGFβ 10 .…”

Section: Discussionmentioning

confidence: 99%

“…This model has been used to investigate gene and protein regulation in the individual cell types (i.e., cancer cells, normal mesothelial or fibroblast cells) after co-culture. In particular, the roles of c-Met 28 , MMP-2 9,29 , Ecadherin 30 , β 1 -integrin 10 , β 3 -integrin 16 , α 5 -integrin 10,31 , and fibronectin 10 in early metastasis have been explored. Additionally, the model has the potential to expand to include more cell types, such as the incorporation of adipocytes 6 .…”

Section: Discussionmentioning

confidence: 99%

“…Immediately underneath this mesotheliallined surface is a layer made predominantly of fibroblasts and extracellular matrix (ECM), which promote cancer cell adhesion and invasion 8 . Ovarian cancer cells secrete factors that induce changes in the mesothelial cell lining that enhance ovarian cancer cell adhesion, invasion, and metastasis 9,10 . Ovarian cancer cells adhere to the mesothelial surface via integrin and CD44-mediated mechanisms ( Figure 1B) [11][12][13][14][15][16] .…”

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confidence: 99%

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Modeling the Early Steps of Ovarian Cancer Dissemination in an Organotypic Culture of the Human Peritoneal Cavity

Peters

Schryver

Lengyel

et al. 2015

JoVE

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The pattern of ovarian cancer metastasis is markedly different from that of most other epithelial tumors, because it rarely spreads hematogenously. Instead, ovarian cancer cells exfoliated from the primary tumor are carried by peritoneal fluid to metastatic sites within the peritoneal cavity. These sites, most notably the abdominal peritoneum and omentum, are organs covered by a mesothelium-lined surface. To investigate the processes of ovarian cancer dissemination, we assembled a complex three-dimensional culture system that reconstructs the lining of the peritoneal cavity in vitro. Primary human fibroblasts and mesothelial cells were isolated from human omentum. The fibroblasts were then mixed with extracellular matrix and covered with a layer of the primary human mesothelial cells to mimic the peritoneal and omental surfaces encountered by metastasizing ovarian cancer cells. The resulting organotypic model is, as shown, used to examine the early steps of ovarian cancer dissemination, including cancer cell adhesion, invasion, and proliferation. This model has been used in a number of studies to investigate the role of the microenvironment (cellular and acellular) in early ovarian cancer dissemination. It has also been successfully adapted to high throughput screening and used to identify and test inhibitors of ovarian cancer metastasis. Video LinkThe video component of this article can be found at

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Upregulation of mesothelial genes in ovarian carcinoma cells is associated with an unfavorable clinical outcome and the promotion of cancer cell adhesion

et al. 2020

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A hallmark of ovarian high‐grade serous carcinoma (HGSC) is its early and massive peritoneal dissemination via the peritoneal fluid. It is generally believed that tumor cells must breach the mesothelium of peritoneal organs to adhere to the underlying extracellular matrix (ECM) and initiate metastatic growth. However, the molecular mechanisms underlying these processes are only partially understood. Here, we have analyzed 52 matched samples of spheroids and solid tumor masses (suspected primary lesions and metastases) from 10 patients by targeted sequencing of 21 loci previously proposed as targets of HGSC driver mutations. This analysis revealed very similar patterns of genetic alterations in all samples. One exception was FAT3 with a strong enrichment of mutations in metastases compared with presumed primary lesions in two cases. FAT3 is a putative tumor suppressor gene that codes for an atypical cadherin, pointing a potential role in peritoneal dissemination in a subgroup of HGSC patients. By contrast, transcriptome data revealed clear and consistent differences between tumor cell spheroids from ascites and metastatic lesions, which were mirrored by the in vitro adherence of ascites‐derived spheroids. The adhesion‐induced transcriptional alterations in metastases and adherent cells resembled epithelial–mesenchymal transition, but surprisingly also included the upregulation of a specific subset of mesothelial genes, such as calretinin (CALB2) and podoplanin (PDPN). Consistent with this finding, calretinin staining was also observed in subsets of tumor cells in HGSC metastases, particularly at the invasive tumor edges. Intriguingly, a high expression of either CALB2 or PDPN was strongly associated with a poor clinical outcome. siRNA‐mediated CALB2 silencing triggered the detachment of adherent HGSC cells in vitro and inhibited the adhesion of detached HGSC cells to collagen type I. Our data suggest that the acquisition of a mesenchymal–mesothelial phenotype contributes to cancer cell adhesion to the ECM of peritoneal organs and HGSC progression.

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Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion

Cited by 258 publications

References 62 publications

Mechanisms and Targets Involved in Dissemination of Ovarian Cancer

Mechanisms and Targets Involved in Dissemination of Ovarian Cancer

Modeling the Early Steps of Ovarian Cancer Dissemination in an Organotypic Culture of the Human Peritoneal Cavity

Upregulation of mesothelial genes in ovarian carcinoma cells is associated with an unfavorable clinical outcome and the promotion of cancer cell adhesion

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