The transmissible agent causing canine transmissible venereal tumor (CTVT) is thought to be the tumor cell itself. To test this hypothesis, we analyzed genetic markers including major histocompatibility (MHC) genes, microsatellites, and mitochondrial DNA (mtDNA) in naturally occurring tumors and matched blood samples. In each case, the tumor is genetically distinct from its host. Moreover, tumors collected from 40 dogs in 5 continents are derived from a single neoplastic clone that has diverged into two subclades. Phylogenetic analyses indicate that CTVT most likely originated from a wolf or an East Asian breed of dog between 200 and 2500 years ago. Although CTVT is highly aneuploid, it has a remarkably stable genotype. During progressive growth, CTVT downmodulates MHC antigen expression. Our findings have implications for understanding genome instability in cancer, natural transplantation of allografts, and the capacity of a somatic cell to evolve into a transmissible parasite.

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SummaryMicroRNA deregulation is frequent in human colorectal cancers (CRCs), but little is known as to whether it represents a bystander event or actually drives tumor progression in vivo. We show that miR-135b overexpression is triggered in mice and humans by APC loss, PTEN/PI3K pathway deregulation, and SRC overexpression and promotes tumor transformation and progression. We show that miR-135b upregulation is common in sporadic and inflammatory bowel disease-associated human CRCs and correlates with tumor stage and poor clinical outcome. Inhibition of miR-135b in CRC mouse models reduces tumor growth by controlling genes involved in proliferation, invasion, and apoptosis. We identify miR-135b as a key downsteam effector of oncogenic pathways and a potential target for CRC treatment.

Jaagsiekte sheep retrovirus (JSRV) is the causative agent of a transmissible lung cancer of sheep known as ovine pulmonary carcinoma. Recently, we have found that the expression of the JSRV envelope (Env) is sufficient to transform mouse NIH 3T3 cells in classical transformation assays. To further investigate the mechanisms of JSRV oncogenesis, we generated a series of envelope chimeras between JSRV and the JSRVrelated endogenous retroviruses of sheep (enJSRVs) and assessed them in transformation assays. Chimeras containing the exogenous JSRV SU region and the enJSRV TM region were unable to transform NIH 3T3 cells. Additional chimeras containing only the carboxy-terminal portion of TM (a region that we previously identified as VR3) of the endogenous envelope with SU and the remaining portion of TM from the exogenous JSRV were also unable to transform NIH 3T3 cells. The VR3 region includes the putative membrane-spanning region and cytoplasmic tail of the JSRV TM glycoprotein; this suggested that the cytoplasmic tail of the JSRV Env mediates transformation, possibly via a cell signaling mechanism. Mutations Y590 and M593 in the cytoplasmic tail of the JSRV envelope were sufficient to inhibit the transforming abilities of these constructs. Y590 and Jaagsiekte sheep retrovirus (JSRV) is the etiological agent of a contagious lung cancer of sheep known as ovine pulmonary carcinoma (OPC) or sheep pulmonary adenomatosis (4,16,30,36). OPC is a naturally occurring disease in most countries of the world and is characterized by the transformation of the differentiated epithelial cells of the lungs, type II pneumocytes and Clara cells (17,33). OPC is being extensively studied for its similarities with a particular type of human lung cancer known as bronchioloalveolar carcinoma (BAC) (17,21,23,33). The causes of BAC are unknown. BAC is not strongly associated with cigarette smoking, and its incidence appears to be increasing in the United States (1,5,6,51). Thus, the JSRV/ OPC model can offer a foundation for understanding the molecular mechanisms of type II pneumocytes and Clara cell transformation, especially considering the role played by retroviruses in the discovery of cellular oncogenes (46). M593 are part of a Y-X-X-M motif that is recognized by the phosphatidylinositol 3-kinase (PI-3K). PI-3K initiates a cell signaling pathway that inhibits apoptosis and is required for a number of mitogens during the G 1 -to-S-phase transition of the cell cycle. PI-3K activatesCell transformation by JSRV is offering a new paradigm for retroviral oncogenesis (45). The JSRV genome does not contain a cell-derived oncogene, which would suggest that JSRV induces cell transformation by insertional activation of protooncogenes (46). However, the incubation period in experimentally inoculated lambs can be as short as 2 to 3 weeks (47, 52), which appears too short for insertional activation to occur. Our recent study showed that the expression of the envelope (Env) protein of JSRV is able to transform rodent fibroblasts in vitro (27). Thus, ...