Each scoring system outperformed tumor size and location, and may be useful when describing the surgical complexity of renal tumors treated with partial nephrectomy.

The contribution of a dysfunctional transforming growth factor-B type II receptor (TGFBRII) to prostate cancer initiation and progression was investigated in an in vivo mouse model. Transgenic mice harboring the dominantnegative mutant TGF-B type II receptor (DNTGFBRII) in mouse epithelial cell were crossed with the TRAMP prostate cancer transgenic mouse to characterize the in vivo consequences of inactivated TGF-B signaling on prostate tumor initiation and progression. Histopathologic diagnosis of prostate specimens from the TRAMP+/DNTGFBRII double transgenic mice revealed the appearance of early malignant changes and subsequently highly aggressive prostate tumors at a younger age, compared with littermates TRAMP+/Wt TGFBRII mice. Immunohistochemical and Western blotting analysis revealed significantly increased proliferative and apoptotic activities, as well as vascularity and macrophage infiltration that correlated with an elevated vascular endothelial growth factor and MCP-1 protein levels in prostates from TRAMP+/DNTGFBRII+ mice. An epithelialmesenchymal transition (EMT) effect was also detected in prostates of TRAMP+/DNTGFBRII mice, as documented by the loss of epithelial markers (E-cadherin and B-catenin) and up-regulation of mesenchymal markers (N-cadherin) and EMT-transcription factor Snail. A significant increase in the androgen receptor mRNA and protein levels was associated with the early onset of prostate tumorigenesis in TRAMP+/DNTGFBRII mice. Our results indicate that in vivo disruption of TGF-B signaling accelerates the pathologic malignant changes in the prostate by altering the kinetics of prostate growth and inducing EMT. The study also suggests that a dysfunctional TGFBRII augments androgen receptor expression and promotes inflammation in early stage tumor growth, thus conferring a significant contribution by TGF-B to prostate cancer progression.

Molecular targeting of apoptotic signaling pathways has been extensively studied in recent years and directed towards the development of effective therapeutic modalities for treating advanced androgenindependent prostate tumors. The majority of therapeutic agents act through intrinsic or mitochondrial pathways to induce programmed cell death. The induction of apoptosis through endoplasmic reticulum (ER) stress pathways may provide an alternative to treat patients. The functional interaction between the BCL-2 family members and regulation of calcium homeostasis in the ER provides a critical link to the life or death outcome of the cell. Apoptosis induction mediated by ER stress-inducing agents is just beginning to be exploited for therapeutic targeting of prostate tumors. Insightful dissection of recently discovered apoptotic signaling pathways that function through the endoplasmic reticulum may identify novel molecules that could effectively target both androgen-dependent and androgen-independent prostate tumors. In this review, we focus on linking ER stress-induced apoptosis to therapeutic targeting of prostate tumors and dissect its cross-talk with the intrinsic and extrinsic apoptotic pathways.

Supplementary Figure 1 from Dysfunctional Transforming Growth Factor-β Receptor II Accelerates Prostate Tumorigenesis in the TRAMP Mouse Model

Supplementary Figure 2 from Dysfunctional Transforming Growth Factor-β Receptor II Accelerates Prostate Tumorigenesis in the TRAMP Mouse Model

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Supplementary Figure 1 from Dysfunctional Transforming Growth Factor-β Receptor II Accelerates Prostate Tumorigenesis in the TRAMP Mouse Model

Supplementary Figure Legends 1-3 from Dysfunctional Transforming Growth Factor-β Receptor II Accelerates Prostate Tumorigenesis in the TRAMP Mouse Model