Schweiger Thomas, Nikolowsky Christoph, Starlinger Patrick, Traxler Denise, Zimmermann Matthias, Birner Peter, Hegedüs Balazs, Dome Balazs, Bergmann Michael, Mildner Michael, Klepetko Walter, Hoetzenecker Konrad, Ankersmit Hendrik Jan
Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Vienna, Austria.
Department of General Surgery, Medical University of Vienna, Vienna, Austria.
PLoS One. 2015 Mar 20;10(3):e0120724. doi: 10.1371/journal.pone.0120724. eCollection 2015.
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.
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.
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.
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.
肺转移在原发性结直肠癌（CRC）患者中很常见。热休克蛋白27（Hsp27）在伤口愈合过程中被激活的成纤维细胞中上调，并且在各种疾病中全身水平升高。癌症相关成纤维细胞（CAFs）也被认为在包括CRC在内的各种恶性肿瘤中作为预后和预测标志物发挥作用。令人惊讶的是，从未在CAFs中评估过Hsp27的表达。因此，我们旨在研究CAFs中Hsp27的表达水平及其在CRC肺转移患者中的临床意义。
通过免疫组织化学评估来自51个肺转移灶（PMs）和33对配对原发性肿瘤的福尔马林固定石蜡包埋（FFPE）组织样本中α-SMA、CD31、Hsp27和波形蛋白的表达，并与临床病理变量相关联。25个肝转移灶作为对照组。此外，通过酶联免疫吸附测定（ELISA）评估肺转移灶切除术前和术后血清样本（n = 10）中循环磷酸化Hsp27和总Hsp27。
在所有PM中均观察到Hsp27的基质表达，并且与α-SMA（P < 0.001）和波形蛋白（P < 0.001）呈强相关。原发性CRC和PM中强烈的基质Hsp27与更高的微血管密度相关。此外，高基质Hsp27和αSMA表达与肺转移灶切除术后无复发生存期降低（分别为P = 0.018和P = 0.008）和总生存期降低（分别为P = 0.031和P = 0.017）相关。转移灶切除术后磷酸化和总Hsp27的血清水平降至与健康对照相当的水平。
在此我们首次描述Hsp27在CRC的肿瘤基质中高表达。基质α-SMA和Hsp27表达与肺转移灶切除术后的临床结果相关。此外，血清Hsp27可能成为CRC转移性疾病的未来标志物。
