Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 22, Pages -Publisher
MDPI
DOI: 10.3390/ijms222212443
Keywords
ovarian cancer; metastasis; mesothelium; mesothelin; cell adhesion; collagen; multicellular aggregates
Funding
- Research Grants [KO1 CA218305, RO1 CA109545, UO1 CA236979]
- National Institutes of Health, National Cancer Institute
- Walther Cancer Foundation Interdisciplinary Interface Training Program
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The glycoprotein mesothelin is overexpressed in ovarian cancer and may play a role in tumor progression by affecting the peritoneal ultrastructure and mesothelial cell surface architecture. Reduced expression of host mesothelin could result in smaller tumor aggregates and decreased peritoneal metastatic tumor burden in mice.
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.
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