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

PLoS One. 2015 Mar 20;10(3):e0120724. doi: 10.1371/journal.pone.0120724. eCollection 2015.

Abstract

Background: Pulmonary 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.

Methods: FFPE 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.

Results: Stromal 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.

Conclusions: Herein 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology*
  • Female
  • Gene Expression
  • HSP27 Heat-Shock Proteins / genetics
  • HSP27 Heat-Shock Proteins / metabolism*
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / mortality
  • Liver Neoplasms / secondary
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / secondary*
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Prognosis
  • Stromal Cells / metabolism*
  • Vimentin / metabolism

Substances

  • ACTA2 protein, human
  • Actins
  • Biomarkers, Tumor
  • HSP27 Heat-Shock Proteins
  • Vimentin

Grants and funding

This study was supported by the Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration and by the Medical University of Vienna. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.