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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of co-inoculation of basement membrane matrix, Matrigel and two human breast cancer cell lines, BT-474 and SK-BR-3, was tested in immune-deficient mice. Both cell lines strongly overexpress c-ErbB-2 protein, whereas only BT-474 is reported to be oestrogen receptor positive. Co-inoculation of Matrigel and BT-474 cells but not of Matrigel and SK-BR-3 cells resulted in tumour formation in bg-nu-xid mice. Oestrogen supplementation greatly enhanced tumorigenicity, but did not seem to be an absolute requirement. In vivo, BT-474 cells grow as a poorly differentiated adenocarcinoma with a doubling time of 9.4 +/- 1.1 days after inoculation into the neck region. A high proliferative activity appears to be compensated by a relatively high rate of cell loss, as BT-474 tumours contain many cells with the typical morphology of apoptotic cell death. Wild-type p53, known to participate in the induction of apoptosis, is absent from the tumours, whereas Bcl-2, known to inhibit apoptosis, is expressed at intermediate levels. BT-474 tumours tend to metastasise to the regional lymph nodes and are capable of forming micrometastatic lesions in the lung. Flow cytometrical analysis of DNA ploidy demonstrated no change in tumours compared with the cell line. Immunohistochemical and flow cytometrical detection of a number of hormone and growth factor receptors, transcription factors, cell adhesion molecules and proteins involved in proliferation and cell death demonstrated no major changes in ploidy and phenotype of tumours compared with the cell line. High expression of the cell-surface molecules c-ErbB-2 and episialin make it a potentially useful model for research in immune therapy.
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PMID:Outgrowth of BT-474 human breast cancer cells in immune-deficient mice: a new in vivo model for hormone-dependent breast cancer. 759 56

Given the plethora of well-documented breast carcinoma-associated antigens in humans including MAGE-1, -2 and -3, mutated p53, p21ras, HER-2/neu and DF3/MUC-1, coupled with evidence that humoral and cytotoxic T-cell responses against these antigens exist, the central dilemma facing tumor immunologists is why the host immune response is so inefficient. One possibility is that tumor cells themselves are either inefficient or ineffective antigen-presenting cells (APCs). The failure of tumor cells to function as APCs may be due to their inability to process and present the antigen, the absence or insufficient numbers of adhesion and costimulatory molecules or, potentially, the secretion of inhibitory cytokines. Therefore, we sought to determine whether human breast cancer cell lines could function as APCs and, if not, to identify mechanism(s) responsible for this defect. Here, we show that human breast cancer cell lines fail to present alloantigen. This defect does not reside in their inherent capacity to present antigen but rather is due to apoptosis of activated T cells induced by exposure to the breast carcinoma-associated mucin antigen, DF3/MUC1. These results support the hypothesis that DF3/MUC1 may contribute to the paucity of clinically significant anticarcinoma-specific immune responses.
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PMID:Breast cancer-associated antigen, DF3/MUC1, induces apoptosis of activated human T cells. 894 37

IIB-BR-G is an undifferentiated, highly heterogeneous, hormone receptor negative human breast cancer cell line previously established in our laboratory from a patient's primary tumor. An in vitro growing cell line (IIB-BR-G) and a xenotransplanted tumor growing in nude mice (IIB-BR-G(NUDE)) were derived. To further characterize these systems, immunocytochemical analysis was performed for differentiation antigens (PEM 200 kDa, CEA, NCA 90 kDa), blood-group related antigens (Le(x), sTn), oncogenes and tumor suppressor gene products (Her-2/neu protein, p53), metastasis-related cathepsin D and CD63/5.01 Ag, and the chemokine monocyte chemotactic protein 1 (MCP-1). Expression of markers was heterogeneous in these different systems. Previously reported karyotypic analysis has shown extensive chromosomal alterations including double min. Searching for oncogene amplification, we detected augmented copy number of c-myc and c-fos, the last one with two rearranged fragments. No amplification was found for c-erbB-2 in the cell line or in IIB-BR-G(NUDE), although this oncogene was amplified in the patient's primary tumor DNA. The differences observed between the patient's tumor, the cell line and the IIB-BR-G(NUDE) tumors are probably due to clonal expansion of cell variants not present in the original tumor. Electron microscopy of IIB-BR-G growing cells revealed epithelial characteristics with abundant dense granules, presumably secretory, distributed all over the cytoplasm and great nuclear pleomorphism. In vitro, IIB-BR-G cells showed a significant number of invading cells by Matrigel assay. After nearly 40 sequential subcutaneous passages of the original xenograft through nude mice, 80% of recipients developed spontaneous metastases, primarily to the lung and lymph nodes. Since this experimental model allowed to analyze changes produced in cancer cells from the primary tumor during adaptation to in vitro and in vivo growth, our results provide novel insights on the behaviour of hormone independent metastatic breast cancer.
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PMID:The human breast cancer cell line IIB-BR-G has amplified c-myc and c-fos oncogenes in vitro and is spontaneously metastatic in vivo. 962 Apr 46

Adenocarcinomas of the breast behave clinically and epidemiologically in ways that show host resistance factors are important for outcome in addition to grade and stage of malignancy. Immune reactivity to autologous tumors is indicated by the general presence of lymphoid infiltration (LI) and regional lymph node changes; however, these changes predict favorable outcome only in non-metastatic disease. LI is characterized by CD4+ and CD8+ tumor infiltrating lymphocytes reflecting latent cell-mediated immunity (CMI). CMI and humoral immune reactivity have been demonstrated to autologous tumor and a variety of tumor-associated antigens (TAA) have been implicated including CEA, HER-2/neu, MAGE-1, p53, T/Tn and MUC-1. Immune incompetence involving CMI is progressive with the stage of breast cancer and is prognostically significant. Immunotherapy of several types has been designed to address this immunodeficiency and the TAAs involved. Animal models have employed drug therapy, cytokine transfection, vaccines with autologous tumor, cytokines like interferon alpha (IFN-alpha) and interleukin-2 (IL-2), TAA tumor vaccines, and immunotoxins with evidence of tumor regression by immunologic means. Immunotherapy of human breast cancer is a rapidly growing experimental area. Positive results have been obtained with natural IFN and interleukins, particularly in combination strategies (but not with high dose recombinant IFN or IL-2), with autologous tumor vaccine (but not yet with transfected autologous tumor); with a mucin carbohydrate vaccine (Theratope) in a combination strategy (but not with mucin core antigen) and with several immunotoxins. Combination strategies involving immunorestoration, contrasuppression, adjuvant, and immunotoxins are suggested for the future.
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PMID:The immunology and immunotherapy of breast cancer: an update. 1023 Aug 72

Tumor-associated antigens that can be recognized by the immune system include the MAGE-family, p53, MUC-1, HER2/neu and p21ras. Despite their expression of these distinct antigens, tumor elimination by the immune system is often inefficient. Postulated mechanisms include insufficient expression of co-stimulatory or adhesion molecules by tumor cells, or defective processing and presentation of antigens on their cell surfaces. Tumor cells may also evade immune attack by expressing CD95 (APO-1/Fas) ligand or other molecules that induce apoptosis in activated T cells. Here we describe RCAS1 (receptor-binding cancer antigen expressed on SiSo cells), a membrane molecule expressed on human cancer cells. RCAS1 acts as a ligand for a putative receptor present on various human cell lines and normal peripheral lymphocytes such as T, B and NK cells. The receptor expression was enhanced by activation of the lymphocytes. RCAS1 inhibited the in vitro growth of receptor-expressing cells and induced apoptotic cell death. Given these results, tumor cells may evade immune surveillance by expression of RCAS1, which would suppress clonal expansion and induce apoptosis in RCAS1 receptor-positive immune cells.
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PMID:Inhibition of cell growth and induction of apoptotic cell death by the human tumor-associated antigen RCAS1. 1042 6

Immortal epithelial cell lines were previously established after transduction of the HPV16-E6E7 genes into primary cultures of normal pancreatic duct epithelial cells. Single clones were isolated that demonstrated near normal genotype and phenotype. The proliferation of HPDE6-E6E7c7 and c11 cells is anchorage-dependent, and they were nontumorigenic in SCID mice. The cell lines demonstrated many phenotypes of normal pancreatic duct epithelium, including mRNA expression of carbonic anhydrase II, MUC-1, and cytokeratins 7, 8, 18, and 19. These cells have normal Ki-ras, p53, c-myc, and p16(INK4A) genotypes. Cytogenetic studies demonstrated losses of 3p, 10p12, and 13q14, the latter included the Rb1 gene. The wild-type p53 protein was detectable at very low levels consistent with the presence of E6 gene product, and the lack of functional p53 pathway was confirmed by the inability for gamma-irradiation to up-regulate p53 and p21waf1/cip1 protein. The p110/Rb protein level was also not detectable consistent with the expression of E7 protein and haploid loss of Rb1 gene. Despite this, the proliferation of both c7 and c11 cells were markedly inhibited by transforming growth factor-beta1. This was associated with up-regulation of p21cip1/waf1 but not p27kip1. Further studies showed that p130/Rb2 and cyclin D3 were expressed, suggesting that p130/Rb2 may have partially assumed the maintenance of G(1) cell cycle checkpoint regulation. These results indicate that except for the loss of p53 functional pathway, the two clones of HPDE6-E6E7 cells demonstrated a near normal genotype and phenotype of pancreatic duct epithelial cells. These cell lines will be useful for future studies on the molecular basis of pancreatic duct cell carcinogenesis and islet cell differentiation.
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PMID:Immortal human pancreatic duct epithelial cell lines with near normal genotype and phenotype. 1107 22

Increasing evidence that non-small cell lung cancer is a systemic disease from the outset confirms the rationale for adjuvant chemotherapy. However, clinical trial evidence of benefit is still awaited. The position is clearer in the case of neoadjuvant therapy because long-term follow up of two trials now shows that patients randomized to chemotherapy before surgery were significantly more likely to survive to 5 years than patients treated with surgery alone. Early data suggest that neoadjuvant chemotherapy based on docetaxel (Taxotere; Aventis, Antony, France) (possibly used sequentially with other agents) may be as effective as older regimens and better tolerated. Because p53 status influences the expression of microtubule-associated proteins and hence the sensitivity of a tumor to taxanes, it is possible that molecular markers could be used to customize chemotherapy to individual patients. Generally, it is becoming clearer that molecular staging is a more sensitive means of demonstrating tumor dissemination than light microscopy. The Cancer and Leukemia Group B is undertaking a prospective study using reverse transcriptase-polymerase chain reaction to detect MUC-1 RNA in bone marrow and hilar and mediastinal lymph nodes removed at resection with the aim of distinguishing between stage I patients likely to remain disease-free for long periods and those at high risk of relapse. A study of small cell lung cancer is using automated fluorescence microscopy to detect keratin-positive cells in the marrow and blood of patients who have a complete response to initial therapy but are nevertheless at high overall risk of relapse. The identification of genetic lesions in a high proportion of patients with non-small cell lung cancer may guide the development of new therapies aimed at increasing rates of apoptosis among tumor cells.
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PMID:Advances in the treatment of non-small cell lung cancer: molecular markers take the stage. 1128 22

The gold standard for clinical outcome of most cancers has been the clinical and pathologic staging of the tumors after surgery. For colorectal cancer (CRC), nodal involvement at the time the primary tumor is resected has been the most reliable indicator of clinical outcome; however, recently, combinations of molecular markers have been reported to be equivalent to pathologic or clinical staging in predicting clinical outcome. In addition, molecular markers can be used in conjunction with clinical or pathologic staging to provide a stronger indicator of clinical outcome than staging alone. We propose that "molecular staging" be added to pathologic staging to aid in predicting clinical outcome and making therapeutic decisions for colorectal cancers, especially stage II and III CRCs. We have reported that the clinical usefulness of most molecular markers varies with the ethnic group of the patients and the anatomic location of CRCs; this complicates the evaluation of prognostic biomarkers and requires much larger numbers of cases to be evaluated. Nevertheless, nuclear accumulation of p53 (p53(nac)) and phenotypic expression of Bcl-2, MUC-1 and p27(kip-1) may be molecular markers approaching acceptance for use in molecular staging of specific subgroups of colorectal cancers.
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PMID:Molecular staging of colorectal cancer in African-American and Caucasian patients using phenotypic expression of p53, Bcl-2, MUC-1 AND p27(kip-1). 1180 99

At the present time, there is no reliable laboratory marker for the diagnosis and prognosis of clear cell renal cell carcinoma (RCC), while about 20% of small tumours detected by modern imaging techniques are benign and the clinical course is difficult to predict with considerable differences for the same stage and same grade. The molecular identification of clear cell RCC cells could satisfy these new requirements in the context of diagnosis of atypical or small renal tumours, allowing a more refined prognostic assessment, which is currently uncertain. Some of the antigens used for molecular diagnosis of clear cell RCC, such as cadherin-6, are present in the normal kidney, while others are newly formed antigens (TuM2PK, MN/CA9, CA12, calpain) or ectopic (PSMA, PSA, KLKI, cytokeratin 7 vimentin) or induce abnormal glycosylation (sialyl Lewis'X, galectins) indicating the malignant nature of the cells. The tumour's capacity for progression is related to dysregulations of the cycle (ras, Pax2, Tiam 1, waf/p21), division (tetracyclines, MIB1, PCNA, Nor Ag), apoptosis (bcl2, p53, CD95/Apo1), and the capacities for tissue invasion (proteases), disorganization (cadherin, catenins) or nidation (ICAM-1, CD44). Finally, chromosomal anomalies (mutations, translocations) also occur. MN/CA9, cadherin-6, vimentin, mucin 1 and DNA content are particularly useful for the diagnosis and/or prognosis of clear cell RCC. These markers can be analysed by extremely sensitive cytometric (flow cytometry, plate cytometry) or molecular methods (RT-PCR, in situ hybridization). These techniques lower the limit of detection of tumour cells in biological products (aspiration cytology, microbiopsy) and eventually in circulating blood. Proteomic and genomic methods (biochips) should considerably accelerate research in this field leading to the development of routine clinical applications.
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PMID:[Molecular and cytometric analysis of renal cell carcinoma cells. Concepts, techniques and prospects]. 1270 48

Many molecular factors related to the carcinogenesis and malignant behavior of pancreatic cancer were identified by investigation of intraductal papillary mucinous tumors (IPMTs). Molecules controlling the G1/S phase, such as p53, p21, p61, and cyclin D1, tumor suppressors including DPC-4, and many other factors such as MUC-1/2 contribute to the promotion of the malignant behavior of IPMTs. They will be important molecular targets for the radical treatment of pancreatic cancer.
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PMID:[Molecular factors promoting carcinogenesis and malignant behavior of intraductal papillary mucinous tumors]. 1285 90


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