Stromal expression of heat-shock protein 27 is associated with worse clinical outcome in patients with colorectal cancer lung metastases.

Thomas Schweiger,Michael Bergmann,Balazs Hegedüs,Matthias Zimmermann,Walter Klepetko,Denise Traxler,Balazs Dome,Konrad Hoetzenecker,Peter Birner,Michael Mildner,Patrick Starlinger,Hendrik Jan Ankersmit,Christoph Nikolowsky,Gabriele Multhoff

doi:10.1371/journal.pone.0120724

Thomas Schweiger, Michael Bergmann + Show 12 more

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https://doi.org/10.1371/journal.pone.0120724

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Abstract

BackgroundPulmonary metastases are common in patients with primary colorectal cancer (CRC). Heat-shock protein 27 (Hsp27) is upregulated in activated fibroblasts during wound healing and systemically elevated in various diseases. Cancer-associated fibroblasts (CAFs) are also thought to play a role as prognostic and predictive markers in various malignancies including CRC. Surprisingly, the expression of Hsp27 has never been assessed in CAFs. Therefore we aimed to investigate the expression level of Hsp27 in CAFs and its clinical implications in patients with CRC lung metastases.MethodsFFPE tissue samples from 51 pulmonary metastases (PMs) and 33 paired primary tumors were evaluated for alpha-SMA, CD31, Hsp27 and vimentin expression by immunohistochemistry and correlated with clinicopathological variables. 25 liver metastases served as control group. Moreover, serum samples (n=10) before and after pulmonary metastasectomy were assessed for circulating phospho-Hsp27 and total Hsp27 by ELISA.ResultsStromal expression of Hsp27 was observed in all PM and showed strong correlation with alpha-SMA (P<0.001) and vimentin (P<0.001). Strong stromal Hsp27 was associated with higher microvessel density in primary CRC and PM. Moreover, high stromal Hsp27 and αSMA expression were associated with decreased recurrence-free survival after pulmonary metastasectomy (P=0.018 and P=0.008, respectively) and overall survival (P=0.031 and P=0.017, respectively). Serum levels of phospho- and total Hsp27 dropped after metastasectomy to levels comparable to healthy controls.ConclusionsHerein we describe for the first time that Hsp27 is highly expressed in tumor stroma of CRC. Stromal α-SMA and Hsp27 expressions correlate with the clinical outcome after pulmonary metastasectomy. Moreover, serum Hsp27 might pose a future marker for metastatic disease in CRC.

Highlights

Colorectal cancer (CRC) is, after lung cancer, the second most common cause of cancer-related death in Europe [1]
Strong stromal Heatshock protein 27 (Hsp27) was associated with higher microvessel density in primary CRC and pulmonary metastases (PM)
High stromal Hsp27 and αSMA expression were associated with decreased recurrence-free survival after pulmonary metastasectomy (P=0.018 and P=0.008, respectively) and overall survival (P=0.031 and P=0.017, respectively)

Summary

Introduction

Colorectal cancer (CRC) is, after lung cancer, the second most common cause of cancer-related death in Europe [1]. Cancer-associated fibroblasts (CAF), and especially activated fibroblasts, play a major role in the tumor-stroma network, similar to dermal fibroblasts in wound healing. This contributed to the description of tumors as “wounds that do not heal” by Dvorak et al in the late 80’s [6]. Due to the expression of αsmooth muscle actin (α-SMA), activated CAF are often described as myofibroblasts. They have been shown to be positive for fibroblast-activation protein-α/seprase, palladin and vimentin [9,10,11,12]. Pulmonary metastases are common in patients with primary colorectal cancer (CRC). We aimed to investigate the expression level of Hsp in CAFs and its clinical implications in patients with CRC lung metastases

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