Host Mesothelin Expression Increases Ovarian Cancer Metastasis in the Peritoneal Microenvironment.

Tyvette S Hilliard,Yueying Liu,Yuliya Klymenko,M Sharon Stack,Elizabeth A Agadi,Zonggao Shi,Kyle Iwamoto,Jeff Johnson,Jing Yang,Madeleine G Yemc,Marwa Asem,Brooke Kowalski,Gifty Marfowaa,Phillip Petrasko

doi:10.3390/ijms222212443

Tyvette S Hilliard, Yueying Liu + Show 12 more

Open Access

https://doi.org/10.3390/ijms222212443

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Abstract

Mesothelin (MSLN), a glycoprotein normally expressed by mesothelial cells, is overexpressed in ovarian cancer (OvCa) suggesting a role in tumor progression, although the biological function is not fully understood. OvCa has a high mortality rate due to diagnosis at advanced stage disease with intraperitoneal metastasis. Tumor cells detach from the primary tumor as single cells or multicellular aggregates (MCAs) and attach to the mesothelium of organs within the peritoneal cavity producing widely disseminated secondary lesions. To investigate the role of host MSLN in the peritoneal cavity we used a mouse model with a null mutation in the MSLN gene (MSLNKO). The deletion of host MSLN expression modified the peritoneal ultrastructure resulting in abnormal mesothelial cell surface architecture and altered omental collagen fibril organization. Co-culture of murine OvCa cells with primary mesothelial cells regardless of MSLN expression formed compact MCAs. However, co-culture with MSLNKO mesothelial cells resulted in smaller MCAs. An allograft tumor study, using wild-type mice (MSLNWT) or MSLNKO mice injected intraperitoneally with murine OvCa cells demonstrated a significant decrease in peritoneal metastatic tumor burden in MSLNKO mice compared to MSLNWT mice. Together, these data support a role for host MSLN in the progression of OvCa metastasis.

Highlights

We investigate the role of host MSLN expression in normal peritoneal tissues, multicellular aggregates (MCAs) formation and ovarian cancer metastasis using an MSLN wild-type (MSLNWT ) and knockout (MSLNKO ) mouse model
Whereas MSLN expression was observed in the mesothelial monolayer of omentum, peri-ovarian fat and lung tissues of MSLNWT mice (Figure 1A), no expression was observed in MSLNKO mice (Figure 1B), verifying knockout of MSLN
Mesothelial cells are the first line of defense to metastasizing cancer cells, providing a frictionless protective barrier between the abdominal organs [27]

Summary

Introduction

MSLN is known to be overexpressed in several human cancers including mesotheliomas, ovarian, pancreatic and gastric. These cancers have a strong preference to metastasize to the peritoneal cavity [1,2,3,4,5,6]. MSLN has been identified as a potential tumor-associated marker in approximately 70% of ovarian cancers [1,6,7,8]. High MSLN expression in human cancer cell lines, including ovarian cancer, has been associated with tumor cell adhesion, increased tumor burden, invasion through mesothelial cells, dissemination within the peritoneal cavity and chemoresistance [1,9,10,11,12]. While tumor-naïve MSLN knockout mice do not present with an abnormal phenotype [13], the contribution of host MSLN expression to peritoneal tumor dissemination has not been explored

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