Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor suppressor protein, p53, protects somatic cells against the accumulation of genomic alterations. Cells harboring mutant or inactivated wild-type p53 protein are at risk for the development of genomic instability. Nuclear accumulation of p53 protein is associated with the stepwise dedifferentiation of papillary carcinoma. We asked whether nuclear p53 accumulation is associated with two known indicators of poor prognosis in papillary carcinoma. We studied 55 consecutive papillary cancers (28 from Russia, and 27 from upstate New York). Nuclear p53 immunoreactivity was assessed using a monoclonal antibody, DO-1, on Formalin-fixed paraffin-embedded specimens. The DNA index was determined by computerized image analysis of Feulgen-stained sections. Nearly all cases were well differentiated and none were associated with distant metastases or extrathyroidal invasion. All primary lesions were less than 4 cm in diameter, and almost all patients were female. Nuclear p53 immunoreactivity was associated with a high-risk group characterized by two known indicators of poor prognosis: age > 50, aneuploid DNA content, or both. In the high-risk group (N = 24) 33% of cases displayed nuclear p53 positivity, compared with only 6% in a low-risk group (N = 31) which lacked both features (P = 0.015, two-tailed Fisher exact test). Nuclear accumulation of immunoreactive p53 protein is associated with two established indicators of poor prognosis in papillary carcinoma of the thyroid. This result is consistent with the idea that aberrations in p53 function are associated with the stepwise loss of differentiation in this cancer.
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PMID:Nuclear p53 immunoreactivity in papillary thyroid cancers is associated with two established indicators of poor prognosis. 755 91

p53 is a tumor suppressor protein that is overexpressed in a variety of human neoplasms, including prostatic adenocarcinoma. Recent studies have demonstrated a significant positive correlation between extent of p53 overexpression and tumor grade in prostatic adenocarcinoma. Because it appears that mutations of p53 might play a role in the pathogenesis of a subset of biologically aggressive prostatic neoplasms, we sought to examine the frequency of p53 overexpression in primary and metastatic prostatic adenocarcinoma. Using a monoclonal antibody (D07) directed against both the wild-type and mutant forms of p53, we examined p53 immunoreactivity in 36 cases of primary prostatic adenocarcinoma, 17 cases of metastatic prostatic adenocarcinoma involving lymph nodes and 15 cases of metastatic prostatic adenocarcinoma involving bone. Twenty-eight percent (10/36) of the primary tumors displayed nuclear staining for p53. Increased p53 immunoreactivity was observed in only 6% (1/16) of prostatic adenocarcinomas with a total Gleason score of 6 or less, as compared with 45% (9/20) of those adenocarcinomas with a Gleason score of 7 or more. Fifty-nine percent (10/17) of the lymph node metastases and 43% (6/14) of the bone metastases displayed nuclear immunoreactivity for p53. Our results indicate that increased p53 expression is positively correlated with increased histologic grade and with the presence of metastatic disease in patients with prostatic adenocarcinoma, and they suggest that mutations of the p53 gene may play a role in mediating the behavior of a biologically aggressive subset of this common neoplasm.
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PMID:p53 immunoreactivity in primary and metastatic prostatic adenocarcinoma. 767 61

PTEN/MMAC1/TEP1 (PTEN) is a tumor suppressor gene that is mutated in a variety of advanced and metastatic cancers, strongly suggests that PTEN alteration is possibly involved in the tumor progression and formation of metastases. However, the roles of PTEN in tumor growth and metastasis and its functional mechanisms are not fully understood. We evaluated the tumor suppressor function of PTEN gene on tumor growth and metastasis in vitro and in vivo. Our results of in vitro soft agar assay and in vivo PTEN-expressing tumor cell growth showed that PTEN inhibited the tumorigenicity of B16F10 melanoma cells. Anti-metastatic function of PTEN was also revealed by experimental pulmonary metastatic animal model. For the further insight into the mechanisms underlying the PTEN-mediated inhibition of tumor metastasis, we have examined the role of PTEN on the secretion of matrix metalloproteinases (MMPs), insulin-like growth factors (IGFs) and the expression of secretory and cellular vascular endothelial growth factor (VEGF) proteins that have been described to contribute to the metastasis of tumor. PTEN significantly lowered MMPs and IGFs secretion and also expression of secretory and cellular VEGF proteins. These results suggest that PTEN tumor suppressor protein inhibits tumorigenicity and metastasis through regulation of MMP, IGFs, and VEGF expression.
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PMID:Suppression of tumorigenicity and metastasis in B16F10 cells by PTEN/MMAC1/TEP1 gene. 1159 33

Four cases of brain metastasis from hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV) are reported in an area not endemic for HBV infection. Two cases are unusual, since cerebral metastases were the only secondary localization. In these cases, no other sites of metastasization were detected either before or immediately following neurosurgical treatment. In all cases the expression of pRB, p53 and p16 tumor suppressor protein was studied with immunohistochemistry, both, in the primary and metastatic lesions. The pRB expression was as follows: in two cases, lack and moderate expression were observed both, in the primary and in the metastases; in the other two, pRB was not detected. In all cases p53 expression was negative both, in the primary and the metastases. P16 expression was moderately expressed in three cases, both in the primary and the metastases. In one case it was absent. Hepatocarcinogenesis is a multistep process, in which several oncogenes and oncosuppressor genes are involved. In four unusual cases of spread to the brain, we evidenced that tumor suppressor protein expression of p16, p53, and particularly pRB (its aberrated expression is usually associated with metastasis) were altered. We also suggest that HBV and its X protein (HBX) might play an important role in such aggressive behavior of the neoplasia.
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PMID:Brain metastasis from hepatocellular carcinoma associated with hepatitis B virus. 1238 72

Human inflammatory breast carcinoma (IBC) is the most malignant type of breast cancer with an extremely poor prognosis. The dog is the unique animal species in which spontaneous inflammatory mammary carcinoma (IC) has been reported, although it is not well documented. The purpose of this study was to characterize histopathologically and immunohistochemically the canine IC, considering associated clinical features. Twenty-one dogs diagnosed with IC and with known clinical and necropsy data were included in the study. Tissue samples from necropsies underwent a histopathological review and an immunohistochemical study (Ki-67, estrogen receptor (ER), progesterone receptor (PR), and P53 tumor suppressor protein). The histological study revealed several types of carcinomas (solid, tubular, papillary, and adenosquamous) and three lipid-rich carcinomas. All tumors were ER negative. Two histological patterns of neoplastic dermal infiltration were observed: tubular/papillary and sarcomatous-like. Dermal sarcomatous-like infiltration was significantly related to previous treatments with progestagens (p = 0.006), primary type of IC (p = 0.03), extreme local pain (p = 0.02), reduced observation of emboli in dermal lymphatic vessels (p = 0.01), and increased expression of p53 (p = 0.001). PR expression was significantly higher in secondary post-surgical IC (p = 0.04). The absence of PR was related to the existence of pulmonary metastases at necropsy (p = 0.04). Canine primary IC is the most aggressive form of this disease with distinct histopathological and immunohistochemical characteristics. Progestins and endocrine-related mechanisms seem to be involved in canine IC development. Canine IC could serve as a spontaneous model for human IBC, particularly in studies concerned with new therapeutics approaches.
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PMID:Canine inflammatory mammary carcinoma: histopathology, immunohistochemistry and clinical implications of 21 cases. 1272 14

Recent research shows that p53 suppresses tumor angiogenesis by transcriptionally activating the alpha(II) collagen prolyl-4-hydroxylase gene. This results in the extracellular release of the potent endogenous angiogenesis inhibitors endostatin and tumstatin from collagens 18 and 4, respectively. The involvement of these inhibitors elucidates a molecular mechanism. By simultaneously repressing a multitude of proangiogenic pathways and by inducing antiangiogenic pathways, a tumor suppressor protein can prevent an incipient tumor from switching to the angiogenic phenotype. Thus, p53 guards the genome from cancer by controlling the three fundamental processes that are critical for growth of a primary tumor and its metastases-tumor cell proliferation, apoptosis, and tumor angiogenesis.
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PMID:Tumor suppression by p53 is mediated in part by the antiangiogenic activity of endostatin and tumstatin. 1700 65

Renal cell carcinoma (RCC) is characterized by organ-specific metastases. The chemokine stromal derived factor-1 (SDF-1/CXCL12) and its receptor CXCR4 have been suggested to regulate organ-specific metastasis in various other cancers. On this basis, we hypothesized that the biological axis of CXCL12 via interaction with its receptor, CXCR4, is a major mechanism for RCC metastasis. We demonstrated that CXCR4 was significantly expressed on circulating cytokeratin+ RCC cells from patients with known metastatic RCC. We detected up-regulation of CXCR4 mRNA and protein levels on a human RCC cell line by either knockdown of the von Hippel-Lindau (VHL) tumor suppressor protein, or incubating the cells under hypoxic conditions. The enhanced CXCR4 expression was mediated through the interaction of the Hypoxia Inducible Factor-1alpha (HIF-1alpha) with the promoter region of the CXCR4 gene. Furthermore, the expression of CXCR4 on human RCC directly correlated with their metastatic ability in vivo in both heterotopic and orthotopic SCID mouse models of human RCC. Neutralization of CXCL12 in SCID mice abrogated metastasis of RCC to target organs expressing high levels of CXCL12; without altering tumor cell proliferation, apoptosis, or tumor-associated angiogenesis. Therefore, our data suggest that the CXCL12/CXCR4 biological axis plays an important role in regulating the organ-specific metastasis of RCC.
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PMID:Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis. 1708 23

Sarcomas represent a heterogeneous group of tumors with a complex and difficult reproducible classification. Their pathogenesis is poorly understood and there are few effective treatment options for advanced disease. Caveolin-1 is a multifunctional scaffolding protein with multiple binding partners that regulates multiple cancer-associated processes including cellular transformation, tumor growth, cell death and survival, multidrug resistance, angiogenesis, cell migration and metastasis. However, ambiguous roles have been ascribed to caveolin-1 in signal transduction and cancer, including sarcomas. In particular, evidence indicating that caveolin-1 function is cell context dependent has been repeatedly reported. Caveolin-1 appears to act as a tumor suppressor protein at early stages of cancer progression. In contrast, a growing body of evidence indicates that caveolin-1 is up-regulated in several multidrug-resistant and metastatic cancer cell lines and human tumor specimens. This review is focused on the role of caveolin-1 in several soft tissue and bone sarcomas and discusses the use of this protein as a potential diagnostic and prognostic marker and as a therapeutic target.
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PMID:Caveolin-1 in sarcomas: friend or foe? 2147 10

Oncolytic herpes simplex virus 1 (HSV-1) viruses armed with immunomodulatory transgenes have shown potential for enhanced antitumor therapy by overcoming tumor-based immune suppression and promoting antitumor effector cell development. Previously, we reported that the new oncolytic HSV-1 virus, OncSyn (OS), engineered to fuse tumor cells, prevented tumor growth and metastasis to distal organs in the 4T1/BALB/c immunocompetent breast cancer mouse model, suggesting the elicitation of antitumor immune responses (Israyelyan et al., Hum. Gen. Ther. 18:5, 2007, and Israyelyan et al., Virol. J. 5:68, 2008). The OSV virus was constructed by deleting the OS viral host shutoff gene (vhs; UL41) to further attenuate the virus and permit dendritic cell activation and antigen presentation. Subsequently, the OSVP virus was constructed by inserting into the OSV viral genome a murine 15-prostaglandin dehydrogenase (15-PGDH) expression cassette, designed to constitutively express 15-PGDH upon infection. 15-PGDH is a tumor suppressor protein and the primary enzyme responsible for the degradation of prostaglandin E2 (PGE2), which is known to promote tumor development. OSVP, OSV, and OS treatment of 4T1 tumors in BALB/c mice effectively reduced primary tumor growth and inhibited metastatic development of secondary tumors. OSVP was able to significantly inhibit the development and accumulation of 4T1 metastatic tumor cells in the lungs of treated mice. Ex vivo analysis of immune cells following treatment showed increased inflammatory cytokine production and the presence of mature dendritic cells for the OSVP, OSV, and OS viruses. A statistically significant decrease in splenic myeloid-derived suppressor cells (MDSC) was observed only for OSVP-treated mice. These results show that intratumoral oncolytic herpes is highly immunogenic and suggest that 15-PGDH expression by OSVP enhanced the antitumor immune response initiated by viral infection of primary tumor cells, leading to reduced development of pulmonary metastases. The availability of the OSVP genome as a bacterial artificial chromosome allows for the rapid insertion of additional immunomodulatory genes that could further assist in the induction of potent antitumor immune responses against primary and metastatic tumors.
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PMID:Oncolytic herpes simplex virus 1 encoding 15-prostaglandin dehydrogenase mitigates immune suppression and reduces ectopic primary and metastatic breast cancer in mice. 2154 7

The roles of many genes in the pathophysiology of lung cancer have been investigated in different studies. Cyclin D1 (CCND1) gene plays a significant role in the transition from G1 to S phase of the cell cycle and in the phosphorylation of retinoblastoma tumor suppressor protein. In this study, we aimed to identify the relationship between CCND1 A870G gene polymorphism with lung cancer. CCND1 A870G genotypes were determined in 75 patients with lung cancer and in 65 control subjects. DNA was isolated from blood samples and then CCND1 A870G gene polymorphism was identified using PCR and RFLP assay. The distribution of CCND1 A870G polymorphism did not show any significant differences in all lung cancer patients and controls. There was no correlation between CCND1 A870G polymorphism and histopathological findings. However, the AA + AG genotype was significantly higher in metastatic patients, when compared with non-metastatic patients. Thus, the results show that CCND1 gene polymorphism may be a predictor for detecting patients with poor survival who having metastatic disease.
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PMID:Relationship between cyclin D1 (A870G) gene polymorphism and lung cancer. 2389 88


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