Analyzing Murine Primary Mesothelial Cell Proteomics to Identify Candidate Proteins Contributing to Gender Differences in Colorectal Cancer Peritoneal Metastatic Receptivity with Aging

Cancer is a disease that predominantly affects older individuals. While age remains one of the most significant risk factors for cancer and metastasis, the biological sex of the host also plays a crucial role in influencing metastasis and survival outcomes.. Specifically in colorectal cancer (CRC), both cancer incidence and deaths from metastatic disease are higher in males relative to females. The study hypothesizes that gender- and/or age-related differences in peritoneal mesothelial cells impact the interaction between tumor and mesothelial cells (MC) early in metastatic dissemination, influencing CRC metastasis success. In a comparative analysis using female or male young mice (3-6 months, equivalent to human 20-30 years old, FY and MY) and aged mice (20-23 months, equivalent to human 60-67 years old, FA and MA) in an intra-peritoneal (ip) metastasis model, results show that aged males exhibit the highest metastatic tumor burden which aligns with human epidemiological data. The results also show CRC selectively targets adipose tissues covered by visceral peritoneum. Additionally, the omentum shows gender-specific differences in aged groups. To further explore these gender and age effects, the study investigates the proteome of murine primary peritoneal mesothelial cells (MPPMCs) isolated from young and aged male and female mice. In each cohort, ~2000 proteins and ~1000 protein groups were identified. Proteomic analysis revealed differences in protein expression based on gender and age, providing baseline data for future studies on how these factors regulate MC homeostasis and influence the initiation of peritoneal diseases. One of the candidate proteins identified, protein tyrosine phosphatase type IVA 1 (Prl-1), has been characterized in its function in CRC metastasis. Prl-1, expressed exclusively in aged male mice, is found to promote CRC metastasis by aiding initial adhesion of tumor cells to mesothelial cells. The study identifies key signaling pathways, including RhoA-GTPase and src-FAK/p130cas, that are activated by Prl-1. A Prl-1 inhibitor, CMPD-43, shows promise in reducing cell adhesion and migration. The findings suggest that targeting Prl-1 could offer new therapeutic avenues to impede CRC progression and metastasis.