Survivin Is a Potential Mediator of Prostate Cancer Metastasis

Abstract

Purpose We examined whether Survivin expression is associated with an increased risk of metastasis in prostate cancer. Methods and Materials A total of 205 patients with T1 (23%) and T2 (77%) prostate cancer were treated with conventional external beam radiation therapy from 1991 to 1993 at the Massachusetts General Hospital. Of the patients, 62 had adequate and suitable-stained tumor material for Survivin analysis. Median follow-up was 102 months (range, 5–127 months). Distant failure was determined on the basis of clinical criteria. In preclinical studies, replication-deficient adenovirus encoding phosphorylation-defective Survivin Thr34 → Ala dominant-negative mutant pAd-S(T34A) or short hairpin RNA (shRNA) was used to inhibit Survivin in prostate cancer models, and the cell motility, morphology, and metastasis were investigated. Results Our correlative data on men with early-stage (T1/T2) prostate cancers treated at Massachusetts General Hospital by definitive radiotherapy indicated that overexpression of Survivin (positive staining in ≥10% cells) was associated with a significantly increased risk for the subsequent development of distant metastasis (p = 0.016) in the univariate analysis. In the multivariate analysis, overexpression of Survivin remained an independent predictor of distant metastasis (p = 0.008). The inhibition of Survivin dramatically inhibited invasiveness of prostate cancer cells in the in vitro invasion assay and spontaneous metastasis in the Dunning prostate cancer in vivo model. Furthermore, attenuation of Survivin resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility. Conclusions This study suggests that Survivin may be a potentially important prognostic marker and promising therapeutic target in metastatic prostate cancer.

Failure of Downregulation of Survivin Following Neoadjuvant Radiochemotherapy in Rectal Cancer Is Associated with Distant Metastases and Shortened Survival

“…Accordingly, this study demonstrates that tumors with a sufficient RCT-induced downregulation of survivin and lower posttreatment expression levels developed significantly fewer cancer relapse and distant metastases, which constitutes an important clinical endpoint in curatively intended treatment of primary rectal cancer. On the contrary, a failure of survivin downregulation was associated with an increased risk to develop distant metastases, that was in line with recent reports on a correlation between a high survivin expression and distant recurrence in T1/T2 prostate (30) and colon cancer (31). This underlines the potential role of survivin in metastatic pathways-beside its antiapoptotic abilities.…”

Immunohistochemical expression and serum level of survivin protein in colorectal cancer patients

“…Survivin as an apoptotic protein may condition tumor aggressiveness and tumor cell invasiveness, including lymph node involvement and distant metastases (22). It has been shown that survivin may determine, via different signaling pathways, the capacity of prostate and breast cancer cells to metastasize (22,23). Single studies have confirmed this potential of survivin in CRC patients.…”

Selinexor (KPT-330) Induces Tumor Suppression through Nuclear Sequestration of IκB and Downregulation of Survivin

“…Survivin is a member of the inhibitors of apoptosis protein family and is overexpressed in most common human cancers including breast, prostate, pancreatic, and hematological malignancies (16)(17)(18)(19)(20)(21). It plays a vital role in oncogenesis by being involved in both cell cycle control and resistance to apoptosis (22).…”