Wnt-5a Protein Expression in Primary Dukes B Colon Cancers Identifies a Subgroup of Patients with Good Prognosis

Abstract

Oncogenic Wnt/B-catenin signaling occurs in a majority of colorectal cancers. In contrast, very little is known about the role of the nontransforming Wnt protein family member Wnt5a in those tumors. In the most common of the three colon cancer stages, Dukes B or lymph node-negative, the outcome is the hardest to predict. We searched for a predictive marker in this group and observed loss of or reduced Wnt-5a expression in 50% of Dukes B tumors. Such Wnt-5a negativity was a strong predictor of adverse outcome, with a relative risk of death of 3.007 (95% confidence interval, 1.336-6.769; P = 0.008) after 5 years in Wnt-5a-negative patients. Furthermore, the median survival time after diagnosis was 109.1 months for patients with Wnt-5a-positive primary tumors but only 58 months for those with Wnt-5a-negative primary tumors. To find a possible biological explanation for these results, we studied the invasive and poorly differentiated human colon cancer cell line, SW480, which does not express Wnt-5a protein and the Wnt-5a-expressing and moderately differentiated Caco2 colon cancer cell line. We found that the addition of recombinant/purified Wnt-5a significantly reduced the migratory capacity of SW480 cells. By comparison, equivalent treatment did not significantly alter migration in the Wnt-5a-expressing Caco2 colon cancer cell line. These findings indicate that the expression of Wnt-5a in primary Dukes B colon cancer tissue constitutes a good prognostic marker for longer survival, which can be explained by the ability of Wnt5a to impair tumor cell migration and thus reduce invasiveness and metastasis. (Cancer Res 2005; 65(20): 9142-6)

Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling

“…Since Wnt-5a acts downstream of β-catenin, Wnt-5a would suppress β-catenin-mediated cell growth specifically. These observations are consistent with previous reports showing that Wnt-5a acts as a tumour suppressor [13,14].…”

“…However, Wnt-5a is able to activate the β-catenin pathway depending on the expression of combinations of distinct receptors [12]. In addition, it has been demonstrated that Wnt-5a inhibits the migration and invasiveness of thyroid tumour and colorectal cancer cell-lines [13,14], whereas, in contrast, it increases the cell motility and invasiveness of melanoma cells and breast cancer cells associated with macrophages [15,16]. Thus, Wnt-5a has been suggested to regulate cell migration, but how it regulates this process is not fully understood.…”

Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling

“…Although Wnt5a has been implicated in invasion and metastasis of several types of tumors (Iozzo et al, 1995;Weeraratna et al, 2002;Dejmek et al, 2005;Kremenevskaja et al, 2005;Kurayoshi et al, 2006;Pukrop et al, 2006), the role of Wnt5a/Ror2 signaling in tumor invasion and metastasis remains elusive. To investigate the role of Wnt5a/Ror2 signaling in tumor invasion, a human osteosarcoma cell line, SaOS-2 cells, that shows invasive properties in vitro and metastasis in mouse models (in vivo) (Dass et al, 2006;Guo et al, 2008), were mainly utilized in this study.…”

“…In fact, antisense Wnt5a mimics Wnt1-mediated transformation of mouse C57MG cells (Olson and Gibo, 1998), and haploinsufficiency of Wnt5a is correlated with the development of B-cell lymphomas in mice (Liang et al, 2003). Furthermore, it has been reported that Wnt5a inhibits cell growth, migration, and invasiveness of thyroid carcinoma cells and colorectal cancer cells (Dejmek et al, 2005;Kremenevskaja et al, 2005). However, there are several lines of evidence indicating that sustained or increased Wnt5a expression is critically involved in various types of cancer (Iozzo et al, 1995;Weeraratna et al, 2002;Kurayoshi et al, 2006;Pukrop et al, 2006).…”

Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase

“…It has been shown that Wnt5a stimulates migration in some cancer cells and that its expression is correlated with the aggressiveness of melanoma, breast cancer, lung cancer and gastric cancer (Weeraratna et al, 2002;Veeman et al, 2003;Huang et al, 2005;Kurayoshi et al, 2006;Pukrop et al, 2006;Kikuchi and Yamamoto, 2008;Yamamoto et al, 2009), suggesting that Wnt5a has oncogenic properties. Other reports indicate that Wnt5a acts as a tumor suppressor based on the finding that Wnt5a has an ability to inhibit proliferation, migration and invasiveness in thyroid tumor and colorectal cancer cell lines (Dejmek et al, 2005;Kremenevskaja et al, 2005). Although the b-catenin-independent pathway activated by Wnt5a is also involved in tumorigenesis, the relationship between the expression of Wnt5a and PCa is not well understood.…”