BERKELEY, CA (UroToday.com) - Epsins are a small family of highly conserved endocytic adaptor proteins that facilitate the regulated endocytosis of ubiquitinated cell surface receptors. Previously, we reported that epsins play an important role in regulating tumor angiogenesis through the internalization and downregulation of VEGFR2. Loss of epsins within the endothelium resulted in the development of dysfunctional tumor vascular networks thus impairing tumor growth. However, solid tumors, such as the ones developed during early prostate cancer progression, depend not only on tumor angiogenesis, but also tumor cell proliferation. Although epsins are reportedly upregulated in various solid tumors including skin, lung, and mammary tumors, little was known about epsins specific role in tumor cells. In our recent study, we report that epsins are significantly upregulated in both human and mouse prostate cancer. Furthermore, we discovered that loss of epsins can protect against the development and progression of prostate cancer using a novel mouse model.
Previously, Hong Chen and colleagues developed mice with floxed epsin 1 and null epsin 2 alleles. By crossing these mice with tamoxifen-inducible Cre recombinase expressing (ERT2-Cre) mice, post-developmental epsin depletion can be achieved. Importantly, epsins 1 and 2 were shown to have redundant function in most cell types, but post-developmental depletion presented a normal phenotype. We took advantage of these mice, crossing them with the spontaneous transgenic adenocarcinoma of mouse prostate (TRAMP) mouse model to establish a genetic epsin depleted prostate cancer model to investigate epsins function in vivo (TRAMP-iDKO). Importantly, the development and progression of prostate cancer in the TRAMP mouse model closely mimics that of human prostate cancer progression. Using this model, we confirmed that epsins expression in the epithelial cells of the prostate tissue acini are significantly increased in the early stages of prostate cancer progression. Moreover, the degree of epsin upregulation tightly correlated with the severity of prostate cancer tumorigenesis. We also discovered that epsins depletion in the TRAMP model significantly hindered tumor incidence and tumor growth resulting in prolonged survival; thus, strongly suggesting that interfering with epsins may provide a protective mechanism to prevent and/or slow prostate cancer progression and metastasis.
In addition to the TRAMP model, we also employed a common xenograft model in which the human prostate cancer cells, LNCaP, were injected subcutaneously and monitored for solid tumor development. Unlike the TRAMP-iDKO model in which epsins are depleted globally upon tamoxifen treatment, thus complicating the interpretation due to epsins potential role in other cell types which may also influence the tumor microenvironment and tumorigenesis, the LNCaP xenograft model allowed us to specifically investigate the effect of epsin depletion on prostate cancer cells. Stable epsin-deficient LNCaP cells were first created by infecting lentivirus-expressing human shRNA targeting epsins 1 and 2, then injecting subcutaneously into the hindquarters of mice. Compared to WT LNCaP cells, we found that the epsin deficiency significantly impaired the formation and growth of a solid LNCaP tumor; further supporting epsins have a specific role in regulating the tumorigenesis of prostate cancer cells.
Collectively, our findings emphasize the importance of epsins in prostate tumorigenesis. Moreover, the fact that epsin depletion was sufficient to increase the survival of TRAMP-iDKO mice compared to wild type TRAMP mice indicates that targeted inhibition of epsins may provide a novel therapeutic target to combat prostate cancer. Importantly, many cancers, including prostate cancer, involve the early development and progression of a solid primary tumor that later metastasizes, causing a significant increase in lethality. Therapeutic interventions, such as the potential inhibition of epsins during the early tumorigenesis, may help to stabilize the rapidly growing primary tumor leading to its effective surgical removal and increased survival in several types of cancer.
Currently, little is known about the transcriptional regulation involved in regulating epsins expression. While the current and previous studies report an upregulation of epsins expression in several types of tumor cells, whether this upregulation is a cause or consequence of tumorigenesis has not been directly established. However, the fact that epsin depletion in prostate cancer cells is sufficient to limit tumorigenesis and that the epsin upregulation in prostate cancer tightly correlates with prostate cancer severity, suggests that the epsins upregulation may be intimately involved in tumor development. In the future, it will be important to determine the transcriptional mechanisms responsible for epsins upregulation in order to establish a direct link between epsins and cancer development. Furthermore, this link may provide essential details for the development of therapeutic epsin inhibitory strategies.
Written by:
Kandice L. Tessneer, PhD, Satish Pasula, PhD, and Hong Chen, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Endocytic adaptor protein epsin is elevated in prostate cancer and required for cancer progression - Abstract
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