Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tonsils seem to be the ideal source of lymphocytes seeding to the mucosa of the respiratory tract. The distribution and engraftment of human lymphocytes injected into mice with severe combined immunodeficiency (SCID) are not well understood. C.B-17 SCID mice were injected intraperitoneally with human tonsillar mononuclear cells (hu-TMC). The hu-TMC-SCID mouse chimeras were subsequently tested for the appearance and distribution of human lymphocytes tagged with H33342 and immunoglobulin-secreting cells in various systemic and mucosal immunocompetent tissues. This was done by fluorescence microscopy of tissue sections for cells supravitally stained before transfer and by an enzyme-linked immunospot assay using cells isolated from murine organs. Most importantly, engraftment of hu-TMC proved to be dependent on the presence of anti-Epstein-Barr virus (EBV) antibody in the donor. hu-TMC engrafted, in decreasing numbers, in the following systemic organs: peritoneal cavity, liver, spleen and bone marrow. Among mucosal tissues tested, hu-TMC were seen in lungs, but not in the intestines. The engraftment of hu-TMC in the lung was more extensive than that in the spleen. These studies demonstrate that hu-TMC engraft in a variety of murine tissues. The striking preference of hu-TMC for the lungs when compared to intestines suggests selective engraftment among distinct mucosal tissues. The hu-TMC-SCID mouse chimera promises to be a unique animal model to study human-mucosa-associated lymphoid cells and EBV-related lymphomagenesis and B cell tumor progression.
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PMID:Distribution and engraftment patterns of human tonsillar mononuclear cells and immunoglobulin-secreting cells in mice with severe combined immunodeficiency: role of the Epstein-Barr virus. 166 36

Angiogenesis plays a fundamental role in human breast tumor progression. In fact, recent findings indicate that vascular density is a prognostic indicator of breast cancer disease status. Evidence is presented that the integrin alpha v beta 3 is not only a marker of human breast tumor-associated blood vessels, but that it plays a significant role in human angiogenesis and breast tumor growth. To assess the role of alpha v beta 3-dependent angiogenesis in the progression of human breast cancer, we examined a SCID mouse/human chimeric model with transplanted full thickness human skin containing alpha v beta 3-negative human breast tumor cells. This tumor induced a human angiogenic response as measured by vascular cell immunoreactivity with monoclonal antibodies LM609 and P2B1 directed to human alpha v beta 3 and CD31, respectively. Intravenous administration of LM609 either prevented tumor growth or markedly reduced tumor cell proliferation within the microenvironment of the human skin. These LM609-treated tumors not only contained significantly fewer human blood vessels but also appeared considerably less invasive than tumors in control animals. These findings demonstrate that alpha v beta 3 antagonists may provide an effective antiangiogenic approach for the treatment of human breast cancer.
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PMID:Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. 756 59

Cell adhesion and migration are important features in tumor invasion, being mediated in part by integrins (extracellular matrix receptors). Integrins are significantly decreased in human prostate cancer. An exception is alpha 6 integrin (laminin receptor) which persists during prostate tumor progression. We have selected high (DU-H) and low (DU-L) expressors of alpha 6 integrin from a human prostate tumor cell line, DU145, to assess experimentally the importance of alpha 6 integrin in tumor invasion. DU-H cells exhibited a four-fold increased expression of alpha 6 integrin on the surface compared to DU-L cells. Both cell types contained similar amounts of alpha 3 and alpha 5 integrin. The DU-H cells contained alpha 6 subunits complexed with both the beta 1 and beta 4 subunits whereas DU-L cells contained alpha 6 complexed only with beta 4. DU-H cells were three times more mobile on laminin as compared to DU-L, but adhered similarly on laminin. Adhesion and migration were inhibited with anti-alpha 6 antibody. Each subline was injected intraperitoneally into SCID mice to test its invasive potential. Results showed greater invasion of DU-H compared to DU-L cells, with increased expression of alpha 6 integrin on the tumor at the areas of invasion. These data suggest that alpha 6 integrin expression is advantageous for prostate tumor cell invasion.
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PMID:Integrin alpha 6 expression in human prostate carcinoma cells is associated with a migratory and invasive phenotype in vitro and in vivo. 758 6

Cell adhesion receptors (eg, integrins and CD44) play an important role in invasion and metastasis during tumor progression. The increase in integrin alpha 4 beta 1 expression on primary melanomas has been reported to significantly correlate with the development of metastases. alpha 4 beta 1 is a cell surface heterodimer that mediates cell-cell and cell-extracellular matrix interactions through adhesion to vascular cell adhesion molecule (VCAM)-1 and to the IIICS region of fibronectin. To test the effects of alpha 4 beta 1 expression on tumor cell metastasis, Chinese hamster ovary cells were transfected with human alpha 4 cDNA. Whereas alpha 4-negative Chinese hamster ovary cells developed only pulmonary metastasis, alpha 4-positive Chinese hamster ovary cells developed bone and pulmonary metastasis in 3 to 4 weeks when injected intravenously into nude mice. Bone metastasis was inhibited by antibody against alpha 4 or VCAM-1. Expression of alpha 3 beta 1, alpha 6 beta 1, or alpha V beta 1 did not induce bone metastasis. Expression of alpha 4 beta 1 also induced bone metastasis in K562 human erythroleukemia cells injected into SCID mice. These results demonstrate that alpha 4 beta 1 can induce tumor cell trafficking to bone, probably via interaction with VCAM-1 that is constitutively expressed on bone marrow stromal cells.
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PMID:Induction of experimental bone metastasis in mice by transfection of integrin alpha 4 beta 1 into tumor cells. 854 26

Prostatic secretions are formed by glands composed of basal and luminal cells and surrounded by a basal lamina. The normal basal cells express several integrins (extracellular matrix receptors) including alpha 2, 3, 4, 5, 6, v, beta 1 and beta 4. These integrin units are polarized at the base of the cells adjacent to the basal lamina. The integrin alpha 6 beta 4 is associated with hemidesmosomal-like structures. The natural history of prostate cancer involves the presence of prostatic intraepithelial neoplasia (PIN) lesions (considered precursor lesions), carcinoma in situ and invasive carcinoma. Hemidesmosomal proteins and the alpha 3 beta 1 and alpha 6 beta 1 integrins (laminin receptors) are retained in the early PIN lesions. Expression of the integrins alpha 2, alpha 4, alpha 5, alpha v and beta 4 is lost in carcinoma. The alpha 3 beta 1 and alpha 6 beta 1 integrins remain associated with invasive carcinoma, the latter being predominant. Integrin expression in carcinoma is diffuse in the plasma membrane and not restricted to the basal aspects of the cell. The alpha 6 beta 1 integrin is fully functional as judged by an ability to adhere to laminin and contains the wild type alpha 6A cytoplasmic signaling domain. The alpha 6 beta 1 integrin is a leading candidate for conferring the invasive phenotype in prostatic carcinoma. Tumor cells with high expression of alpha 6 integrin are more invasive when tested in a SCID mouse model system. Following intraperitoneal injection, the human tumor cells invade the mouse diaphragm and move through the muscle on the surface of the laminin coated muscle cells. Our current working hypothesis is that the production of alpha 6 beta 1 and laminin in human tumor cells contributes to the invasive phenotype. Invasion could occur on the surfaces of laminin coated structures such as the nerves, blood vessels or muscle and account for the known patterns of human prostate tumor progression. Blockage of the expression or function of alpha 6 beta 1 or laminin or preventing the loss of beta 4 would be essential steps in confining the carcinoma to the prostate gland where conventional treatment has already proven effective.
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PMID:The alpha 6 beta 1 and alpha 6 beta 4 integrins in human prostate cancer progression. 854 70

Engraftment of normal or lesional human skin onto nude or SCID (severe combined immunodeficiency) mice has been used as an in vivo experimental model. However, this model has some limitations, such as shrinkage and loss of the grafted skin over time. To improve the experimental model, we have produced two new SCID-lineage mouse strains, BALB/cA-nude-scid (nu/nu, scid/scid) and BALB/cA-beige-scid (bg/bg, scid/scid) mice, by the method of cross intercross. Intraepidermal neoplastic lesions such as Bowen's disease were grafted onto the back of the mice of these strains. The rate of reduction in the size of the grafts was lower on nude-scid and beige-scid mice than on SCID mice. Rates of survival of neoplastic cells in the grafts were higher in nude-scid mice than in SCID and beige-scid mice (SCID mice 38%, nude-scid mice 55%, beige-scid mice 38%). Neoplastic cells of Bowen's disease grafted onto a beige-scid mouse proliferated and invaded the dermis during 233 days of observation, confirming the progression to invasive squamous cell carcinoma from carcinoma in situ. The present study revealed that nude-scid and beige-scide mice newly produced by us provide a very useful in vivo experimental model for the investigation of carcinogenesis and tumor progression in human skin.
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PMID:New immunodeficient (nude-scid, beige-scid) mice as excellent recipients of human skin grafts containing intraepidermal neoplasms. 914 37

The purpose of this study was to develop an experimental model of squamous cell carcinoma that can be used to identify molecular and immunologic changes associated with primary events in malignant transformation, and those associated with metastatic tumor progression in the presence of host homeostatic and immunologic factors. Metastatic variants were derived following in vivo tumor progression of the in vitro transformed squamous cell carcinoma line Pam 212. The parental and metastatic cell lines exhibited similar morphologic features and molecular markers of an epithelial lineage, including an epithelial morphology in culture, cell surface expression of integrin alpha6beta4, and expression of mRNA of cytokeratins K6 and K14. When the growth and metastatic phenotype of the parental and reisolate cell lines was compared, the reisolate cell lines were found to exhibit a greater rate of growth and incidence of metastasis than the parental cell line when reimplanted in vivo. The difference in the growth rate of the parental cell line and the variants observed in vivo was not detected when growth of these lines was compared in vitro, suggesting that the growth advantage and selection of these variants requires tumor-host interaction. The metastatic variants exhibited a similar growth advantage in normal immunocompetent and SCID Balb/c mice, indicating that the growth advantage in vivo is not due to T or B lymphocyte-dependent immune factor(s). We conclude that metastatic variants derived following in vivo tumor progression of an in vitro transformed squamous cell carcinoma line exhibit a differential growth advantage in vivo that requires the host environment. Comparison of these in vitro transformed and in vivo derived metastatic variant cell lines with phenotypic differences in growth and metastasis should prove useful for dissecting the role of tumor and host factor(s) in malignant transformation and metastatic tumor progression of squamous cell carcinoma.
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PMID:Metastatic variants derived following in vivo tumor progression of an in vitro transformed squamous cell carcinoma line acquire a differential growth advantage requiring tumor-host interaction. 924 55

A new xenograft model of multiple myeloma (MM), where growth is strongly regulated by interleukin-6 (IL-6), was established in severe combined immunodeficiency (SCID) mice. In this model, endogenous IL-6 from SCID mice was ineffective at eliciting growth of the established human MM cell line KPMM2; these cells achieved autonomous growth through their autocrine secretion of IL-6. The etiopathology in this disease model is consistent with that of human MM. When greater than 3 x 10(6) KPMM2 cells were injected intravenously (IV), tumors developed in all mice and were predominantly localized in their bone marrow. Tumors were also apparent in the lymph nodes, but absent from other organs. Immunostaining of cell surface antigen (CD38) showed that more than 40% of bone marrow cells in femur were of myeloma origin in the advanced stage of tumor progression (day 37). Histologic analysis of these mice show that bone marrow was largely occupied by plasmablastic cells and bones had developed osteolytic lesions at multiple sites. Concurrently, there was a decrease in bone density throughout the body and a significant increase in ionized plasma calcium. M-protein was detected in the serum within 10 days after transplantation, which correlated with the tumor progression. Between 30 and 40 days after the transplantation, mice presented with a rapid and severe loss of body weight, hind leg paralysis, and fatigue. Subsequently, the mice died within a week. A single IV injection of 0.2 mg humanized anti-IL-6 receptor antibody (hPM1) into mice on the day after tumor transplantation substantially suppressed the elevation of serum M-protein and development of the tumor-associated abnormalities and significantly increased in the life span of tumor-bearing mice. Our data show the usefulness of this model to analyze the pathologic role of IL-6 in MM and the efficacy of targeting the IL-6 receptor in IL-6-dependent KPMM2 cells.
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PMID:New xenograft model of multiple myeloma and efficacy of a humanized antibody against human interleukin-6 receptor. 931 Apr 95

Cell growth and viability are dependent on the function of the multicatalytic proteinase complex (proteasome), a multisubunit particle that affects progression through the mitotic cycle by degradation of cyclins. Exposure of rodent fibroblasts and human lymphoblasts in culture to benzyloxycarbonyl-leucyl-leucyl-phenylalaninal (Z-LLF-CHO), a cell-permeable peptidyl aldehyde inhibitor of the chymotrypsin-like activity of the proteasome, resulted in the induction of apoptosis in a rapid, dose-dependent fashion. Fibroblasts transformed with ras and myc, lymphoblasts transformed by c-myc alone, and a Burkitt's lymphoma (BL) cell line that overexpresses c-Myc were up to 40-fold more susceptible to apoptosis than were either primary rodent fibroblasts or immortalized nontransformed human lymphoblasts, respectively. To determine whether such preferential apoptosis could impact upon tumor growth in vivo, toxicological studies were performed in mice with severe combined immunodeficiency and showed that mice tolerated single interscapular doses of Z-LLF-CHO without unacceptable toxicity. Severe combined immunodeficient mice bearing s.c. BL tumors in the flank were treated interscapularly with Z-LLF-CHO or a comparable dose of the peptidyl alcohol (Z-LLF-OH), which does not induce proteasome inhibition or apoptosis. Single doses of Z-LLF-CHO induced statistically significant (P < 0.0001) early tumor regression and a significant (P < 0.0001) delay in tumor progression. Analysis of tumor specimens revealed increased apoptosis in BL tumors from mice treated with Z-LLF-CHO. These results, showing a 42% tumor growth delay, indicate that proteasome inhibitors have the potential of curbing the growth of a c-myc-related tumor.
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PMID:Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor. 976 62

Malignancy is a common and dreaded complication following organ transplantation. The high incidence of neoplasm and its aggressive progression, which are associated with immunosuppressive therapy, are thought to be due to the resulting impairment of the organ recipient's immune-surveillance system. Here we report a mechanism for the heightened malignancy that is independent of host immunity. We show that cyclosporine (cyclosporin A), an immunosuppressant that has had a major impact on improving patient outcome following organ transplantation, induces phenotypic changes, including invasiveness of non-transformed cells, by a cell-autonomous mechanism. Our studies show that cyclosporine treatment of adenocarcinoma cells results in striking morphological alterations, including membrane ruffling and numerous pseudopodial protrusions, increased cell motility, and anchorage-independent (invasive) growth. These changes are prevented by treatment with monoclonal antibodies directed at transforming growth factor-beta (TGF-beta). In vivo, cyclosporine enhances tumour growth in immunodeficient SCID-beige mice; anti-TGF-beta monoclonal antibodies but not control antibodies prevent the cyclosporine-induced increase in the number of metastases. Our findings suggest that immunosuppressants like cyclosporine can promote cancer progression by a direct cellular effect that is independent of its effect on the host's immune cells, and that cyclosporine-induced TGF-beta production is involved in this.
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PMID:Cyclosporine induces cancer progression by a cell-autonomous mechanism. 1002 62


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