Mesothelin as a Potential Therapeutic Target in Human Cholangiocarcinoma

Yu, Liping; Feng, Mingqian; Kim, Heungnam; Phung, Yen; Kleiner, David E.; Gores, Gregory J.; Qian, Min; Wang, Xin Wei; Ho, Mitchell

doi:10.7150/jca.1.141

Cited by 54 publications

(59 citation statements)

References 29 publications

(66 reference statements)

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“…Here, it is relevant that we could show that the Msln antibody used in our study immunoreacted with both the tumor cell 40‐kDa and 50‐kDa forms of Msln, indicating a commonly shared epitope. Furthermore, similar to others,9, 30 we did not clearly detect evidence of the higher molecular precursor form of Msln (e.g., 69‐71 kDa) in our gels, which could possibly indicate that the furin cleavage is rapid 30. On the other hand, we could show that conversion of the 50‐kDa form to the 40‐kDa form could be achieved by glycosidase treatment.…”

Section: Discussionsupporting

confidence: 80%

“…In addition, in a single‐center clinical study involving nine human cases of biliary cancers, median serum Msln was not elevated over that determined for healthy donors 15. Moreover, only one9 of the human studies published to date used western blotting to assess and validate individual levels of Msln protein being expressed in individual ICC specimens; instead these other studies relied solely on immunostaining to score tumors with high versus low levels of expression.…”

Section: Introductionmentioning

confidence: 95%

“…Msln was reported to be localized by immunohistochemistry to the cholangiocarcinoma cells of human ICC 9. Furthermore, 32%‐37% of analyzed cases of human ICCs have been determined to overexpress Msln,7, 9, 12 which was either not detected or only occasionally and weakly seen in HCC9, 12 and not observed in normal adult human liver tissue samples 9.…”

Section: Introductionmentioning

confidence: 99%

“…In this context, the matricellular glycoprotein periostin (Postn) and the glycosylphosphatidylinositol‐anchored cell membrane glycoprotein mesothelin (Msln) have each been independently suggested as having potential as prognostic factors for human ICC 6, 7. Each may also provide opportunities for the development of novel targeted therapies for ICC 8, 9…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, 32%‐37% of analyzed cases of human ICCs have been determined to overexpress Msln,7, 9, 12 which was either not detected or only occasionally and weakly seen in HCC9, 12 and not observed in normal adult human liver tissue samples 9. Patients with ICC with resected tumors containing ≥50% Msln‐positive cholangiocarcinoma cells exhibited a significantly shorter postoperative survival than those exhibiting Msln negativity or focal positivity,7 suggesting Msln overexpression to be a prognostic factor in patients undergoing hepatectomy for ICC.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model

Manzanares

Campbell

Maldonado

et al. 2017

Hepatology Communications

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Periostin and mesothelin have each been suggested to be predictors of poor survival for patients with intrahepatic cholangiocarcinoma, although the clinical prognostic value of both of these biomarkers remains uncertain. The aim of the current study was to investigate these biomarkers for their potential to act as tumor progression factors when assessed in orthotopic tumor and three‐dimensional culture models of rat cholangiocarcinoma progression. Using our orthotopic model, we demonstrated a strong positive correlation between tumor and serum periostin and mesothelin and increasing liver tumor mass and associated peritoneal metastases that also reflected differences in cholangiocarcinoma cell aggressiveness and malignant grade. Periostin immunostaining was most prominent in the desmoplastic stroma of larger sized more aggressive liver tumors and peritoneal metastases. In comparison, mesothelin was more highly expressed in the cholangiocarcinoma cells; the slower growing more highly differentiated liver tumors exhibited a luminal cancer cell surface immunostaining for this biomarker, and the rapidly growing less differentiated liver and metastatic tumor masses largely showed cytoplasmic mesothelin immunoreactivity. Two molecular weight forms of mesothelin were identified, one at ∼40 kDa and the other, a more heavily glycosylated form, at ∼50 kDa. Increased expression of the 40‐kDa mesothelin over that of the 50 kDa form predicted increased malignant progression in both the orthotopic liver tumors and in cholangiocarcinoma cells of different malignant potential in three‐dimensional culture. Moreover, coculturing of cancer‐associated myofibroblasts with cholangiocarcinoma cells promoted overexpression of the 40‐kDa mesothelin, which correlated with enhanced malignant progression in vitro. Conclusion: Periostin and mesothelin are useful predictors of tumor progression in our rat desmoplastic cholangiocarcinoma models. This supports their relevance to human intrahepatic cholangiocarcinoma. (Hepatology Communications 2018;2:155–172)

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model

Manzanares

Campbell

Maldonado

et al. 2017

Hepatology Communications

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Engineered Fn3 protein has targeted therapeutic effect on mesothelin‐expressing cancer cells and increases tumor cell sensitivity to chemotherapy

Sirois

Deny

et al. 2019

Biotech & Bioengineering

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Mesothelin is a protein expressed at high levels on the cell surface in a variety of cancers, with limited expression in healthy tissues. The presence of mesothelin on tumor tissue correlates with increased invasion and metastasis, and resistance to traditional chemotherapies, through mechanisms that remain poorly understood. Molecules that specifically recognize mesothelin and interrupt its contribution to tumor progression have significant potential for targeted therapy and targeted drug delivery applications. A number of mesothelin‐targeting therapies are in preclinical and clinical development, although none are currently approved for routine clinical use. In this work, we report the development of a mesothelin‐targeting protein based on the fibronectin type‐III non‐antibody protein scaffold, which offers opportunities for applications where antibodies have limitations. We engineered protein variants that bind mesothelin with high affinity and selectively initiate apoptosis in tumor cells expressing mesothelin. Interestingly, apoptosis does not occur through a caspase‐mediated pathway and does not require downregulation of cell‐surface mesothelin, suggesting a currently unknown pathway through which mesothelin contributes to cancer progression. Importantly, simultaneous treatment with mesothelin‐binding protein and chemotherapeutic mitomycin C had a greater cytotoxic effect on mesothelin‐positive cells compared to either molecule alone, underscoring the potential for combination therapy including biologics targeting mesothelin.

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