Impact of Vasectomy on the Development and Progression of Prostate Cancer: Preclinical Evidence

Abstract

Some observational studies have implied a link between vasectomy and an elevated risk of prostate cancer. We investigated the impact of vasectomy on prostate cancer outgrowth, mainly using preclinical models. Neoplastic changes in the prostate were compared in transgenic TRAMP mice that underwent vasectomy vs. sham surgery performed at 4 weeks of age. One of the molecules identified by DNA microarray (i.e., ZKSCAN3) was then assessed in radical prostatectomy specimens and human prostate cancer lines. At 24 weeks, gross tumor (p = 0.089) and poorly differentiated adenocarcinoma (p = 0.036) occurred more often in vasectomized mice. Vasectomy significantly induced ZKSCAN3 expression in prostate tissues from C57BL/6 mice and prostate cancers from TRAMP mice. Immunohistochemistry showed increased ZKSCAN3 expression in adenocarcinoma vs. prostatic intraepithelial neoplasia (PIN), PIN vs. non-neoplastic prostate, Grade Group ≥3 vs. ≤2 tumors, pT3 vs. pT2 tumors, pN1 vs. pN0 tumors, and prostate cancer from patients with a history of vasectomy. Additionally, strong (2+/3+) ZKSCAN3 expression (p = 0.002), as an independent prognosticator, or vasectomy (p = 0.072) was associated with the risk of tumor recurrence. In prostate cancer lines, ZKSCAN3 silencing resulted in significant decreases in cell proliferation/migration/invasion. These findings suggest that there might be an association between vasectomy and the development and progression of prostate cancer, with up-regulation of ZKSCAN3 expression as a potential underlying mechanism.

Effect of Lacking ZKSCAN3 on Autophagy, Lysosomal Biogenesis and Senescence

“…ZKSCAN3 belongs to a family of transcriptional repressor proteins and has been proved to play an essential role in cancer progression via different ways [24][25][26][27][28][29]. For example, Lee et al showed that ZKSCAN3 often over-expressed in uterine cervical cancer and correlated with the poor clinical outcome [30].…”

Vasectomy and Risk of Prostate Cancer: A Systematic Review and Meta-analysis

“…Nevertheless, a statistically significant association is different from causation. Some preclinical studies have tried to explain the association [46] , [47] . Possible explanations for the increased risk of PCa in vasectomized individuals include a decrease in prostatic secretory volume resulting in prolonged exposure to certain carcinogens, an increase in circulating androgens or in the binding capacity of androgen-binding proteins, development of antisemen antibodies that can affect immunological processes, and reduced levels of certain molecules in seminal plasma, such as IGF-1 and IGFBP3, known to be involved in prostate carcinogenesis.…”

Can there be consensus on whether vasectomy is a prostate cancer risk factor?

“…Still, is this a causal finding? A preclinical study supports the positive association of vasectomy and clinically significant prostate cancer, where vasectomized mice had increased incidence of poorly differentiated, increased proliferation of prostate tumors compared to sham mice [8]. As a call to action, the epidemiologic and clinical communities should unite to pool prospective cohort data, and investigate associations of vasectomy and advanced/lethal cancer risk carefully accounting for PSA screening intensity.…”