Survivin, an inhibitor of apoptosis protein, is highly expressed in most cancers and associated with chemotherapy resistance, increased tumor recurrence, and shorter patient survival, making antisurvivin therapy an attractive cancer treatment strategy. However, growing evidence indicates that survivin is expressed in normal adult cells, particularly primitive hematopoietic cells, T lymphocytes, polymorphonuclear neutrophils, and vascular endothelial cells, and may regulate their proliferation or survival. In preclinical animal models, targeted antisurvivin therapies show efficacy without overt toxicity. However, consequences of prolonged survivin disruption in normal cells, particularly those associated with continuous renewal, have not been clearly determined. Understanding the role of survivin in normal versus malignant cells will be important in identifying strategies that maximally disrupt survivin in cancer cells with minimal effect on normal tissues. In this review, we summarize the prognostic relevance of survivin in cancer that justifies the pursuit of antisurvivin therapies and discuss differences in survivin expression between normal and cancer cells. We subsequently review expression of survivin in normal adult tissues and evaluate preclinical antisurvivin therapies reported to date in light of emerging roles for survivin in normal physiology, particularly hematopoiesis, angiogenesis, and immune function. [Mol Cancer Ther 2006;5(5):1087 -98]

The inhibitor-of-apoptosis protein survivin is expressed in most cancers and leukemias and during fetal development, but not in most normal adult tissues. Survivin expression was analyzed in umbilical cord blood (UCB) and adult bone marrow CD34 ؉ cells and in the factordependent MO7e cell line; also investigated was whether survivin expression was regulated by hematopoietic growth factors. Survivin messsenger RNA (mRNA) and protein were expressed in fresh UCB and marrow CD34 ؉ cells. The combination of thrombopoietin, Flt3 ligand, and stem cell factor upregulated survivin expression in CD34 ؉ cells within 24 hours; survivin expression was cell-cycle related and highest during G 2 /M, whereas growth-factor withdrawal resulted in de IntroductionApoptosis is an essential process for cell and tissue homeostasis, and apoptotic effector molecules and disordered apoptosis are involved in various diseases and neoplasias. Survivin is a newly described member of the inhibitor-of-apoptosis (IAP) family characterized by one or more highly conserved baculovirus IAP repeat (BIR) domains. [1][2][3][4] In contrast to other members of the IAP family, which are widely expressed in human tissues, 5,6 survivin is expressed primarily in fetal but not adult tissues, and its expression is aberrantly enhanced in most cancers, including carcinomas of the lung, colon, pancreas, prostate, breast, and stomach, and in most hematopoietic malignancies. 2 Furthermore, survivin is the only IAP whose expression is cell-cycle dependent. 7 Survivin suppresses apoptosis triggered by chemotherapeutic agents, tumor necrosis factor-␣/Fas ligand-induced stimuli, or caspases 3, 7, and 9, 8,9 and elevated expression correlates with poor prognosis in patients with solid tumors, acute leukemia, and lymphoma. 3,4,[10][11][12][13][14][15][16] Overexpression of survivin confers partial factor independence in interleukin-3 (IL-3)-dependent Baf/3 cells 2 and promotes cellcycle progression in hepatocarcinoma cells. 17 Targeting of survivin by antisense or dominant-negative strategies in several transformed cell models results in induction of apoptosis. [18][19][20][21][22] The enhancement of cell survival by survivin results from its binding to the mitotic spindle during G 2 /M in transformed cells, 23 probably in a complex with Cdk4 and p21, 24 which blocks caspase-3 activation. 23,25,26 These findings have led to the belief that survivin overexpression may provide a survival or proliferation advantage for cancer cells and that, because of survivin's limited expression, disrupting survivin interactions may represent a novel cancer therapy. 27 The pattern of survivin expression during development 1 suggests that it may be a general regulator of mitosis, preserving cell fidelity during cell division. However, little is known about regulation of survivin expression in normal adult cells, particularly by growth factors. Survivin is not expressed in most adult human tissues, 2,18 but expression of the mouse survivin homolog, TIAP, is related to proliferation in t...

Mobilized peripheral blood stem cells (PB-SCs