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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review of the action of estrogens and progestagens, the steroids in oral contraceptives, on cells in the endometrium, breast, ovary, cervix and other tissues, regarding possible causative role in cancer development focuses on the level of steroid receptors and observed actions of these hormones on the cellular level. The steroid hormones are thought to interact with cells by binding to a specific receptor on the cell surface, especially estrogen receptors, while progestagen receptors overlap with glucocorticoids and androgens. Oral contraceptives typically have progestin dosages at the plateau of the dose-response curve, but lower estrogen doses may possible improve the cancer risk. Plasma levels are not reliable estimates of estrogen influence; moreover, estrogens are synthesized locally. Carcinogenesis is a multi-stage process requiring cell proliferation, involving an initiating event, and probably promotion agents, resulting in tumor growth. Estrogens increase cell replication in endometrium, and progestins counter it. Breast cancer evolves in several cell types in the epithelium of the terminal ductal lobular unit, with a 20-year latency. Estrogens stimulate ductal growth and progestins its development, and both are required for full stimulation, as in pregnancy. Estrogens usually stimulate cancer growth, but the precise sensitivity to steroids depends on the timing in the life cycle of the tumor. Ovarian cancer is unique in that neoplasms arise from the epithelium, not the hormone-sensitive tissue. Therefore the suppressive effect of steroids on ovarian neoplasia is thought to be via down- regulation of the gonadotropins, prevention of follicular rupture and consequent cell division of the epithelium, or some effect on growth regulating factors. The effect of steroids on the cervix is unclear, since cervical cancers are hormone-resistant, but there may be a step in transformation by human papilloma virus that involves a glucocorticoid- or progesterone receptor. Steroid receptors are also known to exist in tumors of liver, skin, colon, kidney and anterior pituitary, but their function is neoplasia is unknown.
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PMID:Biology of female sex hormone action in relation to contraceptive agents and neoplasia. 165 Dec 4

Two independent lines of experimental evidence are presented in support of the hypothesis that senescence is a normal mechanism of tumor suppression, a homeostatic device designed through evolution to limit cell proliferation irreversibly and thereby to protect the organism against cancer. One set of experiments uses normal human foreskin fibroblasts, transfected at early passage with SV40 DNA and subsequently infected with the K-ras virus. If the cells are immortal prior to infection, they become tumorigenic and make large tumors in nude mice, whereas if they are not immortal, though expressing SV40 T-antigen, they make tiny tumors that senesce in the test mouse after as many doublings as similar cells make in culture. This result demonstrates that immortalization is essential for progressive tumor growth in vivo. The second set of experiments demonstrate that normal human mammary epithelial cells can be immortalized by transfection with viral DNA from human papilloma virus 16 or 18, although these viruses have not been associated with breast cancer. The effective immortalization and other premalignant changes induced by human papilloma virus transfection are accompanied by chromosome changes that may contribute to the partially transformed phenotypes. None of the cloned or pooled transfectants have been tumorigenic in the nude mouse assay. Here, too, immortalization is experimentally separable from tumor-forming ability.
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PMID:Senescence as a mode of tumor suppression. 166 51

Presentation of antigenic peptides by MHC class II molecules to CD4+ T cells is critical to the generation of antitumor immunity. In an attempt to enhance MHC class II antigen processing, we linked the sorting signals of the lysosome-associated membrane protein (LAMP-1) to the cytoplasmic/nuclear human papilloma virus (HPV-16) E7 antigen, creating a chimera (Sig/E7/LAMP-1). Previously, we found that expression of this chimera in vitro and in vivo with a recombinant vaccinia vector targeted E7 to endosomal and lysosomal compartments and enhanced MHC class II presentation to CD4+ T cells compared to vaccinia expressing wild-type E7. In the current study, we tested these recombinant vaccinia for in vivo protection against an E7+ tumor, TC-1, which was derived from primary epithelial cells of C57BL/6 mice cotransformed with HPV-16 E6 and E7 and c-Ha-ras oncogenes. All mice vaccinated with 1 x 10(7) plaque-forming units of wild-type E7-vaccinia showed progressive tumor growth when challenged with a tumorigenic dose of TC-1 tumor cells; in contrast, 80% of mice vaccinated with the chimeric Sig/E7/LAMP1 vaccinia remained tumor free 3 months after tumor injection. Furthermore, treatment with the Sig/E7/LAMP-1 vaccinia vaccine cured mice with small established TC-1 tumors, whereas the wild-type E7-vaccinia showed no effect on this established tumor burden. These findings point out the therapeutic limitations of recombinant vaccinia expressing unmodified tumor antigens. Further, they demonstrate that modifications that reroute a cytosolic tumor antigen to the endosomal/lysosomal compartment can profoundly improve the in vivo therapeutic potency of recombinant vaccines.
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PMID:Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. 854 65

Vaccines harboring genes that encode functional oncoproteins are intrinsically hazardous, as their application may lead to introduction of these genes into normal cells and thereby to tumorigenesis. On the other hand, oncoproteins are especially attractive targets for immunotherapy of cancer, as their expression is generally required for tumor growth, making the arisal of tumor variants lacking these antigens unlikely. Using murine tumor models, we investigated the efficacy of polyepitope recombinant adenovirus (rAd) vaccines, which encode only the immunogenic T cell epitopes derived from several oncogenes, for the induction of protective anti-tumor immunity. We chose to employ rAd, as these are safe vectors that do not induce the side effects associated with, for example, vaccinia virus vaccines. A single polyepitope rAd was shown to give rise to presentation of both H-2 and human leukocyte antigen-restricted cytotoxic T lymphocyte (CTL) epitopes. Moreover, vaccination with a rAd encoding H-2-restricted CTL epitopes, derived from human adenovirus type 5 early region 1 and human papilloma virus type 16-induced tumors, elicited strong tumor-reactive CTL and protected the vaccinated animals against an otherwise lethal challenge with either of these tumors. The protection induced was superior compared with that obtained by vaccination with irradiated tumor cells. Thus, vaccination with polyepitope rAd is a powerful approach for the induction of protective anti-tumor immunity that allows simultaneous immunization against multiple tumor-associated T cell epitopes, restricted by various major histocompatibility complex haplotypes.
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PMID:Protective anti-tumor immunity induced by vaccination with recombinant adenoviruses encoding multiple tumor-associated cytotoxic T lymphocyte epitopes in a string-of-beads fashion. 940 69

There have been many studies for tumor therapy mediated by cytotoxic T lymphocytes (CTL) that recognize tumor-associated antigen. It is generally accepted that CTL responses are induced when antigen is delivered into the cytosol. The pH-sensitive liposomes as vehicles are well known for their capacity to deliver the antigen into the cytosol. In this work, immunization of mice with CTL epitope peptides from Hantaan nucleocapsid protein (M6) or human papilloma virus E7 encapsulated in pH-sensitive liposomes induced effective antigen-specific CTL responses. The CTL responses induced by M6 peptide encapsulated in pH-sensitive liposomes blocked the formation of tumor mass from Hantaan NP transfected B16 melanoma cells in C57BL/6 mice and delayed the growth of preinoculated melanoma cells. During the blockade of the tumor growth, the CTL response was maintained for at least approximately 6 weeks, and the mice secreted Th1 type cytokines such as IL-2 and IFN-gamma. These results suggested that the pH-sensitive liposomes might provide an effective peptide delivery system for CTL-mediated tumor therapy.
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PMID:Development of Th1-mediated CD8+ effector T cells by vaccination with epitope peptides encapsulated in pH-sensitive liposomes. 1139 93

Two recombinant Listeria monocytogenes (rLm) strains were produced that secrete the human papilloma virus-16 (HPV-16) E7 protein expressed in HPV-16-associated cervical cancer cells. One, Lm-E7, expresses and secretes E7 protein, whereas a second, Lm-LLO-E7, secretes E7 as a fusion protein joined to a nonhemolytic listeriolysin O (LLO). Lm-LLO-E7, but not Lm-E7, induces the regression of the E7-expressing tumor, TC-1, established in syngeneic C57BL/6 mice. Both recombinant E7-expressing rLm vaccines induce measurable anti-E7 CTL responses that stain positively for H-2D(b) E7 tetramers. Depletion of the CD8+ T cell subset before treatment abrogates the ability of Lm-LLO-E7 to impact on tumor growth. In addition, the rLm strains induce markedly different CD4+ T cell subsets. Depletion of the CD4+ T cell subset considerably reduces the ability of Lm-LLO-E7 to eliminate established TC-1 tumors. Surprisingly, the reverse is the case for Lm-E7, which becomes an effective anti-tumor immunotherapeutic in mice lacking this T cell subset. Ab-mediated depletion of TGF-beta and CD25+ cells improves the effectiveness of Lm-E7 treatment, suggesting that TGF-beta and CD25+ cells are in part responsible for this suppressive response. CD4+ T cells from mice immunized with Lm-E7 are capable of suppressing the ability of Lm-LLO-E7 to induce the regression of TC-1 when transferred to tumor-bearing mice. These studies demonstrate the complexity of L. monocytogenes-mediated tumor immunotherapy targeting the human tumor Ag, HPV-16 E7.
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PMID:Two Listeria monocytogenes vaccine vectors that express different molecular forms of human papilloma virus-16 (HPV-16) E7 induce qualitatively different T cell immunity that correlates with their ability to induce regression of established tumors immortalized by HPV-16. 1171 14

Epidemiologic studies have implicated estrogenic exposure as well as human papilloma virus (HPV) infection in cervical carcinogenesis, and some studies have suggested that estrogen and HPV may play synergistic roles in cervical tumorigenesis. In this study, we report a novel finding that approximately 35% of cervical carcinomas tested (n = 19) express aromatase, the enzyme responsible for converting androgen to estrogen, the rate-limiting and final step in estrogen biosynthesis. On the other hand, no aromatase expression was detected in precancerous (n = 42) or normal cervical (n = 17) tissue samples. Increased aromatase was associated with increases in estrogen receptors (ER-alpha and ER-beta) and a decrease in progesterone receptor levels, suggesting that in situ estrogen signaling via ER may be involved in tumor growth. Stable overexpression of aromatase in HPV+ cervical cancer cells resulted in increased cellular proliferation, anchorage-independent growth, and ER expression and activity. In contrast, little change in ER was observed in HPV- cells. Steroid hormone receptor expression observed in vitro paralleled that seen in cervical carcinomas expressing aromatase. Aromatase overexpression also induced the expression of cyclin D1, proliferating cell nuclear antigen, and the HPV oncogenes, E6 and E7. Furthermore, the data underscores the importance of steroid receptor (estrogen and progesterone receptors) regulation in cervical carcinogenesis. To our knowledge, this is the first report demonstrating the induction of aromatase expression in cervical carcinomas, and opens the possibility that aromatase inhibitors may be potential therapeutic agents in cervical carcinomas expressing aromatase.
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PMID:Induction of aromatase expression in cervical carcinomas: effects of endogenous estrogen on cervical cancer cell proliferation. 1632 67

Cervical cancer is the second most common malignant neoplasm in women, in terms of incidence and mortality rates worldwide, and is associated with excessive inflammation. This involves the expression of both pro- and anti-apoptotic proteins that have varied effect on tumor growth and metastasis. The objective of the present study was to elucidate the effect of hydrogen peroxide (H2O2) on apoptotic signal molecules in vitro in SiHa and CaSki cell lines expressing the human papilloma virus 16 E6 protein, which causes the ubiquitin-mediated degradation of p53 protein and is thus p53 deficient. The p53 is known to act as a cellular stress sensor and triggers apoptosis. We demonstrate, here, that in HPV 16 positive cell lines apoptosis is triggered by upregulation of p73, which causes activation of pro-apoptotic Bax accompanied by down regulation of anti-apoptotic Bcl xl, release of cytochrome c from mitochondria and activation of caspases-9 and -3.
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PMID:Induction of apoptosis by hydrogen peroxide in HPV 16 positive human cervical cancer cells: involvement of mitochondrial pathway. 1806 Apr 74

Because of the lack of full characterization of tumor associated antigens for solid tumors, whole antigen use is a convenient approach to tumor vaccination. Tumor RNA and apoptotic tumor cells have been used as a source of whole tumor antigen to prepare dendritic cell (DC) based tumor vaccines, but their efficacy has not been directly compared. Here we compare directly RNA electroporation and pulsing of DCs with whole tumor cells killed by ultraviolet (UV) B radiation using a convenient tumor model expressing human papilloma virus (HPV) E6 and E7 oncogenes. Although both approaches led to DCs presenting tumor antigen, electroporation with tumor cell total RNA induced a significantly higher frequency of tumor-reactive IFN-gamma secreting T cells, and E7-specific CD8+ lymphocytes compared to pulsing with UV-irradiated tumor cells. DCs electroporated with tumor cell RNA induced a larger tumor infiltration by T cells and produced a significantly stronger delay in tumor growth compared to DCs pulsed with UV-irradiated tumor cells. We conclude that electroporation with whole tumor cell RNA and pulsing with UV-irradiated tumor cells are both effective in eliciting antitumor immune response, but RNA electroporation results in more potent tumor vaccination under the examined experimental conditions.
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PMID:Whole tumor antigen vaccination using dendritic cells: comparison of RNA electroporation and pulsing with UV-irradiated tumor cells. 1844 82

The role played by B cells in cancer biology is complex and somewhat controversial. Previous studies using genetically engineered mice suggest that B cells may be immunosuppressive and inhibit tumor rejection. However, the effects of B-cell depletion employing an antibody in mice bearing solid tumors has not been tested owing to difficulties in making an effective antimouse CD20 antibody (similar to rituximab). Injection of a newly developed antimouse CD20 antibody was effective in depleting circulating B cells from blood and lymph nodes, although depletion was less complete in the spleen. B-cell depletion slowed the growth of new solid tumors (not expressing CD20) and retarded the growth of established tumors but did not induce tumor regression. However, when the antibody was combined with an active immunotherapy approach using an adenovirus vaccine expressing the human papilloma virus-E7 gene (Ad.E7) in mice bearing TC1 tumors (murine lung cancer cells expressing human papilloma virus-E7), we noted enhanced antitumor effects and increased numbers of tetramer+/CD8+ T cells within the spleens and activated CD8+ T cells within tumors. B-cell depletion using an anti-CD20 antibody was thus effective in retarding tumor growth in multiple solid tumor models and augmenting immunotherapy in a tumor vaccine model. These studies raise the possibility that B-cell depletion may be a useful adjunct in human immunotherapy trials.
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PMID:B-cell depletion using an anti-CD20 antibody augments antitumor immune responses and immunotherapy in nonhematopoetic murine tumor models. 1846 40


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