Purpose: Caspase-14 is unique among caspase family proteases in that its proteolytic processing has been principally associated with epithelial cell differentiation rather than apoptosis or inflammation.We investigated caspase-14 expression in several types of human epithelial malignancy by immunohistochemistry, correlating results with stage, histologic grade, and patient survival. Experimental Design: Tumor-associated alterations in caspase-14 expression were observed for cervical, ovarian, breast, gastric, and colon cancers. Results: In cervical (n = 445), ovarian (n = 91), and colon (n = 106) specimens, expression of caspase-14 was significantly reduced in cancers compared with normal epithelium. Decreases in caspase-14 immunopositivity correlated with the histologic progression of cervical cancer (P < 0.0001, ANOVA). In localized gastric cancers, caspase-14 immunostaining was significantly lower in poorly differentiated tumors compared with well-differentiated tumors (P = 0.02, Pearson's m 2 analysis). Lower caspase-14 expression was associated with advanced clinical stage in ovarian cancer (P = 0.04, ANOVA) and with shorter overall survival among ovarian cancer patients with serous tumors (n = 62) in both univariate (P = 0.005) and multivariate (P = 0.03) analysis. Lower caspase-14 expression correlated with shorter overall survival among patients with T 3 N 0 M 0 stage gastric cancers (n = 94; P = 0.006, log-rank test). In contrast to cervical, ovarian, and colon cancers, caspase-14 expression was increased in ductal carcinoma in situ and invasive cancers compared with normal mammary epithelium (P = 0.001, t test). Conclusions: The findings reveal tumor-specific alterations in caspase-14 expression and suggest that differences in its expression may define subsets of epithelial cancers with distinct clinical behaviors.

Primary human immunodeficiency virus (HIV) infection is characterized by a high-titer viremia that declines precipitously within weeks, most likely as a result of host immune responses. Peripheral blood mononuclear cells (PBMCs) and plasma of four recently HIV-infected individuals were examined to assess the humoral and cellular immune responses potentially involved in early suppression of viral replication. Neutralizing antibodies against autologous viral isolates were low or undetectable in three subjects studied. Cellular cytotoxicity was assayed using Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell lines (B-LCLs) infected with recombinant vaccinia that express HIV-1 proteins. HIV envelope-specific cytotoxicity, which was not mediated by CD8+ cells nor human leukocyte antigen (HLA) class I restricted, developed in PBMCs of all four subjects early after primary infection, but was not correlated with declines in viremia. Gag-specific cytotoxic T lymphocyte (CTL) activity was observed in freshly isolated PBMCs of two subjects, and HIV-specific CTL cell lines were cultured from PBMCs of three subjects shortly after HIV infection. Antibody-dependent cellular cytotoxicity (ADCC) developed early in all four subjects, and was temporally correlated with declines in viremia in two subjects in whom viral load was well characterized. These data suggest that both CTL responses and ADCC may be critical to control of viral replication in acute HIV infection.

Angiogenesis, the formation of blood vessels, is a major factor influencing tumor growth and metastatic capacity, and VEGF is the prototype angiogenic factor. VEGF expression is also found in the dermis and tumor stroma during the course of melanoma progression. Various oncogenes such as c-Src, v-Raf, and Ras, and multiple environmental stimuli, including hypoxia and ultraviolet radiation (UVR), can regulate VEGF expression under certain conditions. We have constructed several cell lines from a radial growth phase, primary human melanoma cell line, WM35. We have stably transfected WM35 cells with mutant activated H-ras, N-ras, dominant negative p53, or empty vector. In this report, we determined how VEGF expression and release from these melanoma cell lines were affected by the following important factors associated with melanoma initiation and progression: hypoxia, UVR, activated Ras, dominant negative p53, and culture conditions mimicking radial growth phase melanoma (monolayer culture) and vertical growth phase melanoma (spheroid culture). We found that hypoxia, but not UVR, up-regulates VEGF mRNA expression and protein release in these melanoma cells. In addition, activated Ras and dominant negative p53 enhances the hypoxia-induced VEGF protein release. We propose that hypoxia-induced VEGF release promotes tumor progression, especially in melanomas with Ras or p53 mutations.

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