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Acute and Chronic Transforming Retroviruses
Published in Pimentel Enrique, Oncogenes, 2020
In female BR6 mice a mammary tumor incidence of over 90% occurs after several pregnancies as a result of milk-borne infection with the mouse MMTV. A high percentage of the tumors contain an acquired MMTV provirus in either of two defined integration region, int-l and int-2, and provirus insertion is accompanied by expression of specific RNA transcripts from these regions.182,183 Region int-l contains four exons capable of coding a 41,000-dalton protein of 370 amino acids.184 The structure of this protein, as deduced from the nucleotide sequence of the four exons of the int-l gene, shows no obvious homology to proteins encoded by known cellular oncogenes but suggests that the protein may be located at the level of a cellular membrane. Activation of int-l should be attributed to an enhancer action of MMTV insertion rather than to a promoter insertion effect of the provirus since the majority of viral insertions occur downstream and far away of the int-l gene.184 A sequence homologous to the mouse int-1 gene is located on human chromosome 12, region q14-pter.185
Bispecific Antibodies
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
David M. Segal, Barbara A. Vance, Giuseppe Sconocchia
Solid tumors have been more refractive to bsAb treatment. Mouse mammary tumors often express mouse mammary tumor virus proteins such as gp52. BsAbs that bind gp52 and mouse CD3 induce activated mouse T cells to specifically kill gp52 + tumor cells in vitro, and to block subcutaneous tumor growth in Winn-type assays (Moreno et al., 1995). However, bsAb treatment was unable to block the growth of established, subcutaneously growing mammary tumors, and only delayed the growth of lung metastases of mammary tumors (Bakacs et al., 1995). In a second syngeneic mouse lung metastasis model (Penna et al., 1994), melanoma cells which were transfected with the human melanoma antigen p97 were injected into mice, and 10 min later mice were given staphylococcal enterotoxin B (SE-B) with or without anti-CD3 × anti-p97 bsAb. Pulmonary metastases were counted on day 14. Combination of SE-B and bsAb significantly reduced the number of metastasis compared to SE-B alone or to a mixture of the unconjugated parental antibodies.
Cancer-Causing Viruses
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Satya P. Gupta, Vertika Gautam
The inspiration for searching for human mammary tumor virus (HMTV) came from the existence of mouse mammary tumor virus (MMTV). MMTV is a milk-transmitted retrovirus such as HTLV, HIV, and BLV (bovine leukemia virus). It belongs to the genus Betaretrovirus and was formerly known as Bittner virus because it was demonstrated by Bittner that MMTV can cause breast cancer in mice (Bittner 1936). Previously, MMTV was also known as “milk factor” because Bittner established the theory that it could be transmitted by cancerous mothers to young mice from a virus in their mother’s milk (Bittner 1936). The majority of mammary tumors in mice are caused by MMTV. From several studies, it has been suggested that an MMTV-related virus, HMTV, sometimes also referred to as Pogo virus, could be associated with human breast cancer (Holland and Pogo 2004). Primary breast cancer cells have been found to produce HMTV particles in vitro (Melana et al. 2007). In fresh breast cancers, the entire HMTV genome, which contains hormone response elements, has also been observed (Liu et al. 2001). HMTV particles in primary breast cancer cells were reported to have morphogenic and molecular characteristics similar to MMTV (Melana et al. 2007). However, further studies failed to corroborate this (Bindra et al. 2007). Also, it could not be well established that HMTV makes any major contribution to the development of breast cancer.
Myeloid deletion of phosphoinositide-dependent kinase-1 enhances NK cell-mediated antitumor immunity by mediating macrophage polarization
Published in OncoImmunology, 2020
Yuexi He, Juan Du, Zhongjun Dong
In solid tumor, NK cell- and CD8+ T cell-mediated antitumor immunity is usually impaired in a suppressive microenvironment, characterized by the high presence of TAMs similar to M2 macrophages.8,48–50 In order to understand whether M2 status causes impaired immune function, we first used a spontaneous PyMT-induced solid tumor mouse model in C57BL/6 background that mimics breast cancer. The transgenic mice specifically express PyMT in mammary gland under the transcriptional control of a long terminal repeat of the mouse mammary tumor virus (MMTV).51 We first noticed that mammalian transgenic expression of PyMT induce breast carcinoma around 12 weeks, and then rapidlyprogress. 18 to 22 weeks, tumor-infiltrating NK cells and CD8+ T cells showed a significant defect in secreting IFN-γ, which is critical to the immunosurveillance by these two types of lymphocytes (Figure 1a,b). Especially in advanced tumors (22 weeks), NK cells were found to be unresponsive to PMA/ionomycin stimulation (Figure 1a), which indicated that at this stage NK cells have lost their function.52–54
The MAP kinase-interacting kinases (MNKs) as targets in oncology
Published in Expert Opinion on Therapeutic Targets, 2019
Jianling Xie, James E. Merrett, Kirk B. Jensen, Christopher G. Proud
The epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells become able to migrate and invade other tissues, making it a key step in tumour metastasis. The transcription factor SNAIL plays a key role in EMT, as does MMP-3. Robichaud et al. [74] showed that CGP57380, which inhibits MNKs (but with limited specificity), reduced polysome-associated while increasing monosome-associated levels of the mRNAs encoding SNAIL and MMP-3, and EMT induced by transforming growth factor β in the NMuMG mouse cell model. MMTV-PyMT 90 (mouse mammary tumour virus-polyoma middle T-antigen) mice provide a widely-used model of spontaneous mammary cancer. By crossing MMTV-PyMT 90 mice with the eIF4ES209A/S209A animals, these authors also showed that phosphorylation of eIF4E promotes both the onset of tumorigenesis and subsequent metastasis. In this study, levels of SMAD2 (a component of TGFβ signalling) were not decreased upon inducible eIF4E knockdown by shRNA in MCF10A cells, in contrast to the findings of an earlier study [75] in which MNKs were reported to promote translation of its mRNA. However, the model used (in the latter case, of glioblastoma multiforme) and other aspects differ.
Breast Cancer Association with Cytomegalo Virus—A Tertiary Center Case-Control Study
Published in Journal of Investigative Surgery, 2019
Anilkumar Surendran, Meer M. Chisthi
On a worldwide basis, breast cancer remains the most commonly diagnosed malignancy in women. Several cancers in humans (for example, cervical cancer, nasopharyngeal cancer liver cancer, and adult T-cell leukemia) are proven to be caused by viruses. Another virus, Mouse Mammary Tumor Virus (MMTV) has been proven to cause breast cancer in mice. Although CMV has been detected in several primary tumors, it is not known whether this virus gives rise to the primary tumor or just remains active in cancer cells. The role of CMV in cancer is unclear but the virus is supposed to exhibit both oncogenic and onco-modulatory properties by expressing some proteins that interfere with cellular processes, changing the tumor micro-environment and by the initiation and promotion of tumor cells.20,21