Wnt5a, a secreted glycoprotein, is a member of the non-canonical Wnt family. It binds to Frizzled (FZD) and Receptor Tyrosine Kinase-Like Orphan Receptor (ROR) family members to activate non-canonical Wnt signaling pathways. Wnt5a is involved in numerous cellular processes such as proliferation, differentiation, migration, adhesion, and polarization, and is crucial for organism development and tissue homeostasis [2,5,6,7].

In colorectal cancer, high Wnt5a + CD68 + /CD68 + TAMs ratio is associated with poor prognosis. Wnt5a can induce M2 polarization of tumor-associated macrophages (TAMs) via regulating the CaKMII-ERK1/2-STAT3 pathway-mediated IL-10 secretion, promoting tumor growth and metastasis [1]. In breast cancer, WNT5A knockdown in HB2 mammary epithelial cells leads to EMT-like changes and increased invasiveness, while WNT5A signaling impairs breast cancer cell migration and invasion through an EMT-independent mechanism by decreasing CD44 expression [3]. In ovarian cancer, Wnt5a protein expression is upregulated and linked to poor prognosis, and downregulating Wnt5a suppresses ovarian cancer cell migration and invasion [4].

In summary, Wnt5a plays diverse and context-dependent roles in different cancers. Its functions range from promoting tumor progression, as seen in colorectal and ovarian cancers, to inhibiting cell migration and invasion in breast cancer. Studies on Wnt5a, including those using gene-knockout models (implied by functional studies), have enhanced our understanding of cancer development mechanisms, potentially offering new therapeutic targets for cancer treatment.

References:

1. Liu, Qing, Yang, Chaogang, Wang, Shuyi, Liu, Keshu, Xiong, Bin. 2020. Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression. In Cell communication and signaling : CCS, 18, 51. doi:10.1186/s12964-020-00557-2. https://pubmed.ncbi.nlm.nih.gov/32228612/

2. Tufail, Muhammad, Wu, Changxin. 2023. WNT5A: a double-edged sword in colorectal cancer progression. In Mutation research. Reviews in mutation research, 792, 108465. doi:10.1016/j.mrrev.2023.108465. https://pubmed.ncbi.nlm.nih.gov/37495091/

3. Prasad, Chandra Prakash, Chaurasiya, Shivendra Kumar, Guilmain, William, Andersson, Tommy. 2016. WNT5A signaling impairs breast cancer cell migration and invasion via mechanisms independent of the epithelial-mesenchymal transition. In Journal of experimental & clinical cancer research : CR, 35, 144. doi:10.1186/s13046-016-0421-0. https://pubmed.ncbi.nlm.nih.gov/27623766/

4. Zhou, Weijian, Mei, Jie, Gu, Dingyi, Wang, Huiyu, Liu, Chaoying. 2021. Wnt5a: A promising therapeutic target in ovarian cancer. In Pathology, research and practice, 219, 153348. doi:10.1016/j.prp.2021.153348. https://pubmed.ncbi.nlm.nih.gov/33540373/

5. Bueno, Maura Lima Pereira, Saad, Sara Teresinha Olalla, Roversi, Fernanda Marconi. 2022. WNT5A in tumor development and progression: A comprehensive review. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 155, 113599. doi:10.1016/j.biopha.2022.113599. https://pubmed.ncbi.nlm.nih.gov/36089446/

6. Shi, Ya-Ning, Zhu, Neng, Liu, Chan, Liao, Duan-Fang, Qin, Li. 2017. Wnt5a and its signaling pathway in angiogenesis. In Clinica chimica acta; international journal of clinical chemistry, 471, 263-269. doi:10.1016/j.cca.2017.06.017. https://pubmed.ncbi.nlm.nih.gov/28641961/

7. Bhatt, Pooja M, Malgor, Ramiro. 2014. Wnt5a: a player in the pathogenesis of atherosclerosis and other inflammatory disorders. In Atherosclerosis, 237, 155-62. doi:10.1016/j.atherosclerosis.2014.08.027. https://pubmed.ncbi.nlm.nih.gov/25240110/