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Vimentin Expression in Tumor Microenvironment Predicts Survival in Pancreatic Ductal Adenocarcinoma: Heterogeneity in Fibroblast Population

Annals of Surgical Oncology volume 26, pages 4791–4804 (2019)Cite this article

Abstract

Background

The tumor microenvironment, including cancer-associated fibroblasts (CAFs), plays various clinical roles in cancer growth. CAFs are a heterogeneous population and express a variety of mesenchymal markers. However, the clinical roles for CAFs expressing different markers in pancreatic ductal adenocarcinoma (PDAC) remain unknown.

Methods

We reviewed 67 resected PDAC patients who had not received preoperative therapy. Each primary tumor was analyzed for vimentin and α-smooth muscle actin (α-SMA) expression by immunohistochemical and dual immunofluorescence staining.

Results

There was no correlation between the percentage of cells expressing vimentin and α-SMA in the tumor stroma (Pearson’s correlation coefficient: r = 0.171). Higher vimentin expression (p = 0.018) was associated with significantly shorter overall survival in PDAC patients. Using dual immunofluorescence staining, vimentin-positive CAFs were divided into two subpopulations: co-expression of α-SMA, and no co-expression of α-SMA. In PDAC, the level of co-expression had no effect on survival using univariate analysis (median survival time, 33.3 months for low co-expression vs. 18.2 months for high co-expression; log-rank, p = 0.143). However, multivariate analysis clarified that CAFs expressing vimentin alone was an independent predictor of poor survival (p = 0.014; hazard ratio, 2.305; 95% confidence interval, 1.181–4.497).

Conclusions

Vimentin-positive CAFs without co-expression of α-SMA were associated with poor survival in PDAC, and CAFs possessed molecular and functional heterogeneity in this disease.

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Acknowledgment

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Affiliations

  1. Department of Surgery, Shiga University of Medical Science, Otsu-shi, Shiga, Japan

    Hiromitsu Maehira MD, Toru Miyake MD, PhD, Hiroya Iida MD, PhD, Aya Tokuda MD, Haruki Mori MD, Daiki Yasukawa MD, Tomoharu Shimizu MD, PhD & Masaji Tani MD, PhD

  2. Department of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan

    Ken-ichi Mukaisho MD, PhD

Authors
  1. Hiromitsu Maehira MD
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  2. Toru Miyake MD, PhD
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  3. Hiroya Iida MD, PhD
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  4. Aya Tokuda MD
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  5. Haruki Mori MD
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  6. Daiki Yasukawa MD
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  7. Ken-ichi Mukaisho MD, PhD
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  8. Tomoharu Shimizu MD, PhD
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  9. Masaji Tani MD, PhD
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Contributions

H. Maehira and T.M. described and designed the article. M.T. revised the article. H. Maehira and K.M performed microscopic evaluation. H.I., A.T., H. Mori, D.Y., and T.S. performed the surgery and postoperative management. All authors read and approved the final article.

Corresponding author

Correspondence to Toru Miyake MD, PhD.

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Supplementary Fig.

 1 Receiver operating characteristic (ROC) curve of Vimentin expression rate (a), co-expression rate of α-SMA and Vimentin (b), single α-SMA expression (c), and single Vimentin expression (d) for alive or dead analysis at the median follow-up time. The areas under the ROC are 0.604 (95% CI, 0.448–0.760), 0.538 (95% CI, 0.396–0.681), 0.655 (95% CI, 0.524–0.786), and 0.598 (95% CI, 0.452–0.743), respectively (TIFF 191 kb)

Supplementary Fig.

 2 Kaplan–Meier analyses of RFS (a) and OS (b), according to the CAF number in the tumor, and of RFS (c) and OS (d), according to the CAF number per tumor area, as determined by dual IF staining. CAF cancer-associated fibroblasts; RFS recurrent-free survival; OS overall survival; IF immunofluorescence (TIFF 106 kb)

Supplementary Fig.

 3 Kaplan–Meier analyses of RFS (a) and OS (b) according to the degree of α-SMA single expression in the central part of the tumor stroma, as determined by dual IF staining. RFS recurrent-free survival; OS overall survival; α-SMA alpha-smooth muscle actin; IF immunofluorescence (TIFF 74 kb)

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Maehira, H., Miyake, T., Iida, H. et al. Vimentin Expression in Tumor Microenvironment Predicts Survival in Pancreatic Ductal Adenocarcinoma: Heterogeneity in Fibroblast Population. Ann Surg Oncol 26, 4791–4804 (2019). https://doi.org/10.1245/s10434-019-07891-x

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