Skip to main content

Advertisement

SpringerLink
Log in

Mesothelin Expression is Correlated with Chemoresistance in Stage IV Colorectal Cancer

  • Translational Research
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

References

  1. 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.

    Article  Google Scholar 

  2. 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.

    Article  Google Scholar 

  3. 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.

    Article  CAS  Google Scholar 

  4. 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.

    Article  Google Scholar 

  5. 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.

  6. 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.

    Article  Google Scholar 

  7. 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.

    Article  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. 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.

    Article  Google Scholar 

  11. 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.

    Article  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. 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.

    Article  Google Scholar 

  15. 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.

    Article  CAS  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. 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.

    Article  CAS  Google Scholar 

  18. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–74.

    Article  CAS  Google Scholar 

  19. 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.

    Article  CAS  Google Scholar 

  20. 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.

    Article  CAS  Google Scholar 

  21. 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.

    Article  CAS  Google Scholar 

  22. Chang MC, Chen CA, Hsieh CY, et al. Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway. Biochem J. 2009;424:449–58.

    Article  CAS  Google Scholar 

  23. 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.

    Article  CAS  Google Scholar 

  24. 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.

    Article  Google Scholar 

  25. 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.

    Article  CAS  Google Scholar 

  26. 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.

    Article  CAS  Google Scholar 

  27. 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.

    Article  CAS  Google Scholar 

  28. 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.

    Article  CAS  Google Scholar 

  29. Shah AN, Summy JM, Zhang J, et al. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol. 2007;14:3629–37.

    Article  Google Scholar 

Download references

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.

Funding

No sources of financial or material support were used to assist in the preparation of this study.

Author information

Authors and Affiliations

  1. Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan

    Ken Nagata MD, Eiji Shinto MD, PhD, Takehiro Shiraishi MD, Masato Yamadera MD, PhD, Yoshiki Kajiwara MD, PhD, Satsuki Mochizuki PhD, Koichi Okamoto MD, PhD, Takahiro Einama MD, PhD, Yoji Kishi MD, PhD & Hideki Ueno MD, PhD

Authors
  1. Ken Nagata MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eiji Shinto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takehiro Shiraishi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masato Yamadera MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshiki Kajiwara MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satsuki Mochizuki PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Koichi Okamoto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takahiro Einama MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoji Kishi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hideki Ueno MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eiji Shinto MD, PhD.

Ethics declarations

Diclosures

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.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-021-10507-y

Search

Navigation