Primary Cilia Are Lost in Preinvasive and Invasive Prostate Cancer

Abstract

Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Little is known about the role of primary cilia in preinvasive and invasive prostate cancer. However, reduced cilia expression has been observed in human cancers including pancreatic cancer, renal cell carcinoma, breast cancer, cholangiocarcinoma, and melanoma. The aim of this study was to characterize primary cilia expression in preinvasive and invasive human prostate cancer, and to investigate the correlation between primary cilia and the Wnt signaling pathway. Human prostate tissues representative of stages of prostate cancer formation (normal prostate, prostatic intraepithelial neoplasia (PIN), and invasive prostate cancer (including perineural invasion)) were stained for ciliary proteins. The frequency of primary cilia was determined. A decrease in the percentage of ciliated cells in PIN, invasive cancer and perineural invasion lesions was observed when compared to normal. Cilia lengths were also measured to indirectly test functionality. Cilia were shorter in PIN, cancer, and perineural invasion lesions, suggesting dysfunction. Primary cilia have been shown to suppress the Wnt pathway. Increased Wnt signaling has been implicated in prostate cancer. Therefore, we investigated a correlation between loss of primary cilia and increased Wnt signaling in normal prostate and in preinvasive and invasive prostate cancer. To investigate Wnt signaling in our cohort, serial tissue sections were stained for β-catenin as a measure of Wnt signaling. Nuclear β-catenin was analyzed and Wnt signaling was found to be higher in un-ciliated cells in the normal prostate, PIN, a subset of invasive cancers, and perineural invasion. Our results suggest that cilia normally function to suppress the Wnt signaling pathway in epithelial cells and that cilia loss may play a role in increased Wnt signaling in some prostate cancers. These results suggest that cilia are dysfunctional in human prostate cancer, and increase Wnt signaling occurs in a subset of cancers.

Primary cilia are increased in number and demonstrate structural abnormalities in human cancer

“…Conversely, primary cilia were neither increased nor decreased compared with normal tissue in lobular and ductal breast carcinomas or in gastric or prostatic adenocarcinoma. Interestingly, two recent studies report reduced numbers of primary cilia in prostatic cancer11 and breast cancer 12. The present study also found reduced frequency of primary cilia in these two cancer types (3.74% in prostatic cancer vs 8.07% in normal prostate and 1.8% and 4.44% in breast cancer vs 5.92% in normal breast tissue) but the results were not significant (p values 0.204 for prostatic and 0.061 and 0.169 for ductal cancer and lobular breast cancer, respectively).…”

“…Primary cilia repress canonical Wnt signalling by constraining Jouberin (Jbn) to the ciliary axoneme and β-catenin to the basal body, limiting their entry into the nucleus and therefore downstream activation 11. The primary cilia also act as a signalling hub for the Hedgehog pathway, with both an oncogenic role and an inhibitory role depending on the cancer-initiating event18 and can facilitate the Hedgehog pathway by the expression of smoothened (smo) at the primary cilium, which is vital for Hedgehog signalling 4.…”

Primary Cilia in Tumor Biology: The Primary Cilium as a Therapeutic Target in Cholangiocarcinoma

“…Other tumors presenting loss or decreased cilia expression include prostate, breast, melanoma, chondrosarcoma/enchondromas, and rhabdomyosarcoma, but the mechanisms involved in ciliary loss in these cancers remain to be elucidated [26, 38–43]. …”

Depletion of primary cilium in acral melanoma

“…Here, we found a significant decrease in the ciliation rate of Sox10+ cells of acral melanoma (9%) vs acral nevi (74%) ( P ‐value <0.001), suggesting that loss of primary cilium may be either a causal or correlative factor during acral melanoma biogenesis. In addition, these data portray cilia loss as a common cellular feature of both acral melanoma and CMM as well as other types of malignancy . Nonetheless, the number of cases studied was small, and we believe our study should be interpreted as a pilot initiative, with findings that require validation by a larger study.…”