Expression and Function of Survivin in Canine Osteosarcoma

Abstract

Osteosarcoma has a high mortality rate and remains in need of more effective therapeutic approaches. Survivin is an inhibitor of apoptosis family member protein that blocks apoptosis and drives proliferation in human cancer cells where it is commonly elevated. In this study, we illustrate the superiority of a canine osteosarcoma model as a translational tool for evaluating survivin-directed therapies, owing to the striking similarities in gross and microscopic appearance, biologic behavior, gene expression, and signaling pathway alterations. Elevated survivin expression in primary canine osteosarcoma tissue correlated with increased histologic grade and mitotic index and a decreased disease-free interval (DFI). Survivin attenuation in canine osteosarcoma cells inhibited cell-cycle progression, increased apoptosis, mitotic arrest, and chemosensitivity, and cooperated with chemotherapy to significantly improve in vivo tumor control. Our findings illustrate the utility of a canine system to more accurately model human osteosarcoma and strongly suggest that survivin-directed therapies might be highly effective in its treatment. Cancer Res; 72(1); 249-59. Ó2011 AACR.

Survivin expression in canine lymphomas in relation with proliferative markers

“…MI and PI assessed as the number of mitotic figures and the percentage of Ki67-positive cells, respectively. According to our knowledge only a few such studies have been previously conducted on canine osteosarcomas (Bongiovanni et al 2012a, Davies et al 2012, Shoeneman et al 2012) and sebaceous lesions (Bongiovanni et al 2012b) and has not been previously reported in canine NHLs.…”

“…Such discrepancy in survivin localization in neoplastic cells have also been described in canine tumors. For example, in osteosarcoma cytoplasmic or nuclear staining reaction was predominant, as observed by Bongiovanni et al (2012a) and Shoeneman et al (2012), respectively.…”

“…Immunohistochemical studies have revealed expression of this protein in some canine tumors including transitional cell carcinomas of urinary bladder (Rankin et al 2008), cutaneous tumors (Bongiovanni et al 2009(Bongiovanni et al , 2012b and osteosarcomas (Bongiovanni et al 2012a, Davies et al 2012, Shoeneman et al 2012.…”

Survivin suppressor (YM155) enhances chemotherapeutic efficacy against canine histiocytic sarcoma in murine transplantation models

“…Survivin is expressed in considerably high levels during the G2/M phase of the cancer cell division cycle and supports an excessive cell-growth process (Shoeneman et al, 2012). Therefore, YM155 exhibited a highly synergistic effect when combined with taxane agents or radiotherapies, coupled with a high sensitivity in the G2/M phase, as compared with the corresponding monotherapies (Iwasa et al, 2008;Nakahara et al, 2011;Shen et al, 2012;Yamanaka et al, 2011).…”

“…Survivin is a member of the IAP family that controls cell division and apoptosis (Shoeneman et al, 2012). Enhanced survivin expression in several cancer cell lines has been suggested to support increased cancer cell survival by mobilizing the function and expression of other IAP family members, and to be a part of the mechanism by which chemoresistance is acquired (Kanwar et al, 2013;Rödel et al, 2012).…”