Stromal Expression of Heat-Shock Protein 27 Is Associated with Worse Clinical Outcome in Patients with Colorectal Cancer Lung Metastases

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.

Mesenchymal MAPKAPK2/HSP27 drives intestinal carcinogenesis

“…Interestingly, we found that α-SMA + cells, including smooth muscle cells and myofibroblasts, were the cells that showed the highest levels of phosphorylated Hsp27 both in the normal mucosa and tumors, and that this property was dependent on MK2 expression. This is consistent to previous reports on the expression pattern of Hsp27 in CRC, as well as its coexpression with α-SMA in CRC lung metastases (32). Interestingly, phosphorylation of Hsp27, which is increased in blood endothelial cells, is not influenced by MK2 deletion, which indicates that the function of the p38/ MK2/Hsp27 pathway is cell and tissue dependent.…”

“…5F). In agreement with these data, staining with antibodies against phospho-Hsp27 has revealed a stromal pattern of Hsp27 activation in human tumors (32). These results indicate that MK2 regulates activation of Hsp27 in intestinal mesenchymal cells, both in homeostasis and cancer in the intestine.…”

In vitro evaluation of aspirin-induced HspB1 against heat stress damage in chicken myocardial cells

“…At sufficient levels, HspB1 has been widely considered to serve multiple protective functions, but its overabundance may protect mutant cells from programmed death or even lead to cancer. A previous study associated stromal expression of HspB1 (Hsp27) with cancer development (Schweiger et al 2015). Some researchers believe that inappropriate expression of Hsps, especially HspB1, can block apoptosis pathways and actively be involved in various processes such as tumor cell proliferation, invasion, metastases, and death (Lianos et al 2015).…”

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

“…Other functions of HSP27 include direct interference with apoptotic pathway and regulation of cytoskeleton dynamics [15,16]. Whereas its primary function is to promote cellular homeostasis under stressor conditions, overexpression of HSP27 is closely related to tumorigenesis, metastasis, and invasiveness in various cancers such as head and neck squamous cell carcinoma, pediatric acute myeloid leukemia, breast cancer, and colorectal cancer [17][18][19][20]. HSP27 has been identified as an important regulator of the Salvador-Warts-Hippo pathway (Hippo pathway), which controls tumor initiation, progression, cancer stem cell programming, and metastasis.…”