Abstract
Background
Mesothelin (MSLN) is a cell-surface glycoprotein present on mesothelial cells; its expression in several epithelial cancers generally portends an unfavorable prognosis. We investigated MSLN as a surrogate chemopredictive biomarker and examined the impact of MSLN expression in stage IV colorectal cancer (CRC).
Methods
We recruited 254 patients with CRC who received systemic chemotherapy following primary tumor resection between 2000 and 2019. Resected specimens were immunostained for MSLN and stratified by MSLN expression. The associations of tumor MSLN expression with tumor response in metastatic lesions and survival were evaluated.
Results
Of the 247 patients with stage IV CRC, 41 (16.1%) and 213 (83.9%) had high and low MSLN expression, respectively. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, the investigator-assessed objective response rate was 22.0% in the high MSLN expression group and 45.5% in the low MSLN expression group (p = 0.0050). The disease control rates in these groups were 65.9% and 85.9%, respectively (p = 0.00019). In the patients with high MSLN expression, the conversion rate among those with initially unresectable metastases was 0% versus 14% in the patients with low MSLN expression (p = 0.0053). The median overall survival (OS) was 1.5 years (95% confidence interval [CI] 1.1–2.8) in the high MSLN expression group versus 2.6 years (95% CI 2.2–3.0) in the low MSLN expression group. The 3-year OS rates in these groups were 23.5 and 41.5%, respectively (p = 0.0120).
Conclusions
High MSLN expression is correlated with chemoresistance and poor prognoses in stage IV CRC.
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References
de Rosa A, Gomez D, Hossaini S, et al. Stage IV colorectal cancer: outcomes following the liver-first approach. J Surg Oncol. 2013;108:444–9.
Lam VW, Laurence JM, Pang T, et al. A systematic review of a liver-first approach in patients with colorectal cancer and synchronous colorectal liver metastases. HPB (Oxford). 2014;16:101–8.
Jegatheeswaran S, Mason JM, Hancock HC, Siriwardena AK. The liver-first approach to the management of colorectal cancer with synchronous hepatic metastases: a systematic review. JAMA Surg. 2013;148:385–91.
Shao YC, Chang YY, Lin JK, et al. Neoadjuvant chemotherapy can improve outcome of colorectal cancer patients with unresectable metastasis. Int J Colorectal Dis. 2013;28:1359–65.
Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg. 2004; 240: 644-657; discussion 657-648.
Lam VW, Spiro C, Laurence JM, et al. A systematic review of clinical response and survival outcomes of downsizing systemic chemotherapy and rescue liver surgery in patients with initially unresectable colorectal liver metastases. Ann Surg Oncol. 2012;19:1292–301.
Yun HR, Lee WY, Lee WS, et al. The prognostic factors of stage IV colorectal cancer and assessment of proper treatment according to the patient’s status. Int J Colorectal Dis. 2007;22:1301–10.
Kobayashi H, Kotake K, Sugihara K. Prognostic scoring system for stage IV colorectal cancer: is the AJCC sub-classification of stage IV colorectal cancer appropriate? Int J Clin Oncol. 2013;18:696–703.
Hirokawa F, Asakuma M, Komeda K, et al. Is neoadjuvant chemotherapy appropriate for patients with resectable liver metastases from colorectal cancer? Surg Today. 2019;49:82–9.
Shiraishi T, Shinto E, Yamadera M, et al. Significance of mesothelin expression in preoperative endoscopic biopsy specimens for colorectal cancer prognosis. Oncotarget. 2020;11:3807–17.
Prieve MG, Moon RT. Stromelysin-1 and mesothelin are differentially regulated by Wnt-5a and Wnt-1 in C57mg mouse mammary epithelial cells. BMC Dev Biol. 2003;3:2.
Bharadwaj U, Marin-Muller C, Li M, et al. Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation. Carcinogenesis. 2011;32:1013–24.
Shiraishi T, Shinto E, Nearchou IP, et al. Prognostic significance of mesothelin expression in colorectal cancer disclosed by area-specific four-point tissue microarrays. Virchows Arch. 2020;477:409–20.
Shinto E, Hashiguchi Y, Ueno H, et al. Pretreatment CD133 and cyclooxygenase-2 expression as the predictive markers of the pathological effect of chemoradiotherapy in rectal cancer patients. Dis Colon Rectum. 2011;54:1098–106.
Christensen M, Katballe N, Wikman F, et al. Antibody-based screening for hereditary nonpolyposis colorectal carcinoma compared with microsatellite analysis and sequencing. Cancer. 2002;95:2422–30.
Shinto E, Tsuda H, Ueno H, et al. Prognostic implication of laminin-5 gamma 2 chain expression in the invasive front of colorectal cancers, disclosed by area-specific four-point tissue microarrays. Lab Invest. 2005;85:257–66.
Shiraishi T, Shinto E, Mochizuki S, et al. Mesothelin expression has prognostic value in stage II/III colorectal cancer. Virchows Arch. 2019;474:297–307.
Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–74.
Yamada Y, Takahari D, Matsumoto H, et al. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2013;14:1278–86.
Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1065–75.
Hassan R, Blumenschein GR, Moore KN, et al. First-in-human, multicenter, phase I dose-escalation and expansion study of anti-mesothelin antibody-drug conjugate anetumab ravtansine in advanced or metastatic solid tumors. J Clin Oncol. 2020;38:1824–35.
Chang MC, Chen CA, Hsieh CY, et al. Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway. Biochem J. 2009;424:449–58.
Bharadwaj U, Marin-Muller C, Li M, et al. Mesothelin confers pancreatic cancer cell resistance to TNF-alpha-induced apoptosis through Akt/PI3K/NF-kappaB activation and IL-6/Mcl-1 overexpression. Mol Cancer. 2011;10:106.
He X, Wang L, Riedel H, et al. Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells. Mol Cancer. 2017;16:63.
Arumugam T, Ramachandran V, Fournier KF, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–8.
Hoshino H, Miyoshi N, Nagai K, et al. Epithelial-mesenchymal transition with expression of SNAI1-induced chemoresistance in colorectal cancer. Biochem Biophys Res Commun. 2009;390:1061–5.
Uchibori K, Kasamatsu A, Sunaga M, et al. Establishment and characterization of two 5-fluorouracil-resistant hepatocellular carcinoma cell lines. Int J Oncol. 2012;40:1005–10.
Yang AD, Fan F, Camp ER, et al. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res. 2006;12:4147–53.
Shah AN, Summy JM, Zhang J, et al. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol. 2007;14:3629–37.
Acknowledgments
This study was supported in part by the Japan Society for the Promotion of Science KAKENHI (18 K08721). The authors would like to thank Y. Hasumi for their expert technical assistance.
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No sources of financial or material support were used to assist in the preparation of this study.
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Ken Nagata, Eiji Shinto, Takehiro Shiraishi, Masato Yamadera, Yoshiki Kajiwara, Satsuki Mochizuki, Koichi Okamoto, Takahiro Einama, Yoji Kishi and Hideki Ueno disclose they have no significant relationships with or financial interest in any commercial companies related to this article.
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Nagata, K., Shinto, E., Shiraishi, T. et al. Mesothelin Expression is Correlated with Chemoresistance in Stage IV Colorectal Cancer. Ann Surg Oncol 28, 8579–8586 (2021). https://doi.org/10.1245/s10434-021-10507-y
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DOI: https://doi.org/10.1245/s10434-021-10507-y