SUMMARY Prostate cancer (PCa) is heterogeneous and contains both differentiated and undifferentiated tumor cells, but the relative functional contribution of these two cell populations remains unclear. Here we report distinct molecular, cellular, and tumor-propagating properties of PCa cells that express high (PSA+) and low (PSA−/lo) levels of the differentiation marker PSA. PSA−/lo PCa cells are quiescent and refractory to stresses including androgen deprivation, exhibit high clonogenic potential, and possess long-term tumor-propagating capacity. They preferentially express stem cell genes and can undergo asymmetric cell division generating PSA+ cells. Importantly, PSA−/lo PCa cells can initiate robust tumor development and resist androgen ablation in castrated hosts, and harbor highly tumorigenic castration-resistant PCa cells that can be prospectively enriched using ALDH+CD44+α2β1+ phenotype. In contrast, PSA+ PCa cells possess more limited tumor-propagating capacity, undergo symmetric division and are sensitive to castration. Together, our study suggests PSA−/lo cells may represent a critical source of castration-resistant PCa cells.
In the host cell, retroviral DNAs exist in three main forms: unintegrated linear, unintegrated circular, and integrated (the provirus). High levels of unintegrated forms of retroviral DNA often correlate with superinfection and accompanying cytopathic effects, as, for example, in the case of feline acquired immunodeficiency. In culture, HIV-1 infection also results in high levels of unintegrated viral DNA although direct correlations with cytopathicity have not been made. The low frequency of HIV-1-infected cells in patients has made it difficult to determine the structure of the viral DNA in fresh tissue samples from AIDS patients by standard methods such as Southern hybridization. The PCR technique however, which allows the detection of viral DNA at levels far below that possible by other hybridization methods is, in its conventional form, of limited use for quantitative analysis. To study the amount and form of HIV-1 DNA in primary tissue of AIDS patients we have therefore modified the PCR method. Our results indicate that each of the three species of viral DNA are detectable in blood and brain of AIDS patients, and that in autopsy samples from patients with HIV encephalitis there is a considerably higher proportion of unintegrated viral DNA.
Vascular endothelial cell growth inhibitor (VEGI), a member of the tumor necrosis factor (TNF) family, is an endothelial cell-specific inhibitor of angiogenesis. Overexpression by cancer cells of a secretable VEGI fusion protein resulted in abrogation of xenograft tumor progression, but overexpression of full-length VEGI was completely without effect. This finding indicates that secretion is essential for VEGI action. Here we report the identification of two new VEGI isoforms consisting of 251 and 192 amino acid residues. Both isoforms show endothelial cell-specific expression and share a C-terminal 151-residue segment with the previously described VEGI, which comprises 174 residues. The isoforms are generated from a 17 kb human gene by alternative splicing. Their expression is regulated in parallel by inflammatory cytokines TNF-alpha and interferon-gamma. VEGI-251, the most abundant isoform, contains a putative secretion signal. VEGI protein is detected in conditioned media of endothelial cells and VEGI-251-transfected mammalian cells. Overexpression of VEGI-251 in endothelial cells causes dose-dependent cell death. VEGI-251-transfected cancer cells form xenograft tumors of reduced growth rate and microvessel density compared with tumors of empty vector transfectants. These findings support the view that endothelial cell-secreted VEGI may function as an autocrine inhibitor of angiogenesis and a naturally existing modulator of vascular homeostasis.
CD4− epithelial cells covering mucosal surfaces serve as the primary barrier to prevent human immunodeficiency virus type 1 (HIV-1) infection. We used HIV-1 vectors carrying the enhanced green fluorescent protein gene as a reporter gene to demonstrate that HIV-1 can infect some CD4− human epithelial cell lines with low but significant efficiencies. Importantly, HIV-1 infection of these cell lines is independent of HIV-1 envelope proteins. The Env-independent infection of CD4− cells by HIV-1 suggests an alternative pathway for HIV-1 transmission. Even on virions bearing Env, a neutralizing antibody directed against gp120 is incapable of neutralizing the infection of these cells, thus raising potential implications for HIV-1 vaccine development.
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