Diffuse mesothelin expression leads to worse prognosis through enhanced cellular proliferation in colorectal cancer

Our plain-English summary of Diffuse mesothelin expression leads to worse prognosis through enhanced cellular proliferation in colorectal cancer, by S. Inoue, T. Tsunoda, M. Riku, et al (Oncology Letters, 2020).

The study

• Authors: S. Inoue, T. Tsunoda, M. Riku, H. Ito, A. Inoko, H. Murakami, M. Ebi, N. Ogasawara, I. Pastan, K. Kasugai, K. Kasai, H. Ikeda, S. Inaguma
• Journal: Oncology Letters
• Published: 2020;19(3):1741-1750
• Cited by: 44 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelin (MSLN) is a glycophosphatidylinositol (GPI)-linked cell surface protein that is highly expressed in several types of malignant tumor, including malignant pleural mesothelioma, ovarian cancer and pancreatic adenocarcinoma. Recently, a comprehensive immunohistochemical study using MN-1 monoclonal antibody identified a significant number of colorectal tumors in which MSLN was expressed. However, the clinicopathological profiles and survival of patients with MSLN-positive colorectal cancer have not been fully analyzed. In the current study, the expression of MSLN in 270 primary and 44 metastatic colorectal tumors was immunohistochemically analyzed to determine the clinical usefulness of MSLN immunohistochemistry and to identify potential candidates for future anti-MSLN therapy. In vitro experiments using colon cancer cell lines were performed to investigate the biological significance of MSLN expression in tumors. The results of univariate analyses identified a significant correlation between MSLN expression and females (P=0.0042). Furthermore, an inverse correlation between MSLN expression and solid/sheet-like proliferation (P=0.014) was also revealed. Additionally, overall survival was significantly shorter in patients with diffuse luminal/membranous expression of MSLN (P=0.018). Multivariable Cox hazards regression analysis revealed diffuse MSLN expression (hazard ratio, 2.26; 95% confidence interval, 1.04-4.91; P=0.039) as a potential risk factor. When comparing primary CRCs and the metastasis of each, a weakly positive correlation was identified for MSLN positivity (% positive cells; R=0.484; P<0.0001). The in vitro experiments revealed a positive role for MSLN in colon cancer cell proliferation. Thus, MSLN immunohistochemistry may be useful in the prognostication of patients with CRC. The results demonstrated that significant numbers of patients with MSLN-positive CRC exhibiting metastasis could be targeted by anti-MSLN therapies.

Copyright: © Inoue et al.

In plain English

This study did not look at asbestos exposure. It studied mesothelin, a cell-surface protein also found in malignant pleural mesothelioma, in colorectal cancer. The authors stained 270 primary colorectal tumors removed at Aichi Medical University Hospital, Japan, from 2009 to 2012, plus 52 normal colon samples and 44 metastases from 27 patients. They also ran laboratory experiments on colon cancer cell lines. Mesothelin was found in 53% (142/270) of the tumors and in none of the normal samples. It was more common in tumors from female patients. In patients whose tumors showed mesothelin on all tumor cells ("diffuse" expression), 5-year survival was 47.8%, compared with 75.6% in other patients. In a multivariable analysis, diffuse expression had a hazard ratio of 2.26 (95% CI 1.04 to 4.91). In cell lines, adding mesothelin increased cell growth and reducing it slowed growth. The authors concluded that mesothelin staining had a significant impact on predicting outcome in colorectal cancer. They also concluded that patients with mesothelin-positive tumors and metastases might be candidates for anti-mesothelin therapies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Immunohistochemical study of stored surgical tumor samples with survival analysis, plus in vitro experiments on colon cancer cell lines
• Who was studied: 270 primary colorectal tumors resected at Aichi Medical University Hospital, Japan, 2009 to 2012, with 52 adjacent normal colonic mucosa samples and 44 metastases from 27 patients; patients followed for up to 90 months; seven colon cancer cell lines
• Exposure: No asbestos or fiber exposure was studied. The factor examined was mesothelin (MSLN) protein expression in tumors, with diffuse expression defined as 100% of cells positive on the lumen/cell membrane
• Main results:
  • Mesothelin was detected in 53% (142/270) of primary colorectal cancers
  • None of the 52 normal colonic mucosa samples expressed mesothelin
  • Mesothelin positivity was higher in tumors from female patients (P=0.0042)
  • Tumors with solid/sheet-like growth tended to show less mesothelin expression than tumors with tubular structures (P=0.014)
  • Five-year survival was 47.8% in patients with diffuse mesothelin expression vs. 75.6% in others (P=0.018)
  • The worse outcome with diffuse expression was significant in male patients (P=0.010) but not in female patients (P=0.312)
  • In multivariate Cox analysis, diffuse mesothelin expression was a potential independent risk factor: HR 2.26, 95% CI 1.04 to 4.91, P=0.039
  • Mesothelin positivity in primary tumors and their metastases showed a weakly positive correlation (R=0.484, P less than 0.0001)
  • In cell lines, forced mesothelin expression increased proliferation or survival under serum-reduced conditions, and knocking mesothelin down suppressed proliferation
  • Cyclin A labeling (a marker of dividing cells) was higher in 21 tumors with diffuse mesothelin expression than in 30 arbitrarily selected tumors with negative or partial expression (P=0.011)
• The authors' conclusion: The authors concluded that mesothelin staining had a significant impact on prognosis prediction in colorectal cancer patients, that mesothelin-driven cell proliferation was important for worse prognosis, and that mesothelin-positive patients with metastases might be candidates for mesothelin-targeting therapies
• Limitations the authors state:
  • The lack of a clear link between sex and mesothelin in cell lines might reflect the small number of cell lines analyzed
  • Positivity was lower than in the authors' earlier study, possibly because a different staining system was used
  • It is unclear whether ethnicity affects mesothelin expression

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Prognosis, Colorectal Cancer, Pleural Mesothelioma, Ovarian Cancer, Adenocarcinoma, Monoclonal Antibody, Immunohistochemistry.

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