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

The aggressive clinical behavior of melanoma suggests that the developmental origins of melanocytes in the neural crest might be relevant to their metastatic propensity. Here we show that primary human melanocytes, transformed using a specific set of introduced genes, form melanomas that frequently metastasize to multiple secondary sites, whereas human fibroblasts and epithelial cells transformed using an identical set of genes generate primary tumors that rarely do so. Notably, these melanomas have a metastasis spectrum similar to that observed in humans with melanoma. These observations indicate that part of the metastatic proclivity of melanoma is attributable to lineage-specific factors expressed in melanocytes and not in other cell types analyzed. Analysis of microarray data from human nevi shows that the expression pattern of Slug, a master regulator of neural crest cell specification and migration, correlates with those of other genes that are important for neural crest cell migrations during development. Moreover, Slug is required for the metastasis of the transformed melanoma cells. These findings indicate that melanocyte-specific factors present before neoplastic transformation can have a pivotal role in governing melanoma progression.
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PMID:The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. 1614 32

Pancreatic adenocarcinoma (PC) is an aggressive malignancy resistant to standard treatment modalities. Previously, we have reported that cancer-associated Sm-like protein (CaSm) contributes to the neoplastic transformation of PC. In this study, we utilized a recently established preclinical model of PC to determine if molecular targeting of CaSm can serve as the basis for a novel PC therapy. In a subcutaneous tumor model, intratumoral administration of an adenoviral vector encoding CaSm antisense RNA (Ad-alphaCaSm) significantly inhibited Panc02 tumor growth. Furthermore, in a metastatic tumor model, systemic administration of Ad-alphaCaSm resulted in a significant decrease in the number of hepatic metastases and increased survival time. We assessed the efficiency of in vivo delivery and observed significant levels of vector transduction in tissues containing PC, as well as a bystander effect that was amplifying the efficacy of CaSm gene therapy. This bystander effect was also active in vitro and was shown to be at least partially independent of host-related mechanisms. We conclude that CaSm antisense gene therapy is an effective novel therapy for PC and that the antitumor efficacy is dependent on both direct and bystander mechanisms.
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PMID:Bystander effect contributes to the antitumor efficacy of CaSm antisense gene therapy in a preclinical model of advanced pancreatic cancer. 1622 92

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumours with various clinical characteristics. These tumours generally exhibit complex karyotypes. Few studies of genomic imbalances have been performed exclusively in subgroups of larynx cancer samples at different stages of the disease. In the present study, chromosomal gains and losses were investigated in 52 larynx tumours, by using comparative genomic hybridization (CGH). The mean number of observed alterations was 37.7 per tumour. The most common sites of losses were 1p, 13q, Xp, and the most common gains were located in 1p, 9q, 16q. The overall number of gains was negatively associated with cancer grading. G1 tumours were also characterized by a higher frequency of deletions in 13q32 and amplifications in 1q23, than tumours in other grades (p < 0.05). The frequency of losses of 13q22 also positively associated with tumour size. There was no association between the frequency of losses in 13q and the presence of lymph node metastases at the time of diagnosis. Another statistically significant association was observed for gains at 1q22-23 and tumour size (p < 0.01). No statistically significant difference in the frequency of most common imbalances was detected between primary tumours with lymph node metastases and those without metastases. In conclusion, we discovered a significant involvement of 13q deletions in the progression of larynx cancer. All the other significant changes observed in the present study were reported previously as being important for HNSCC progression. It seems that multiple genes are disrupted in the process of neoplastic transformation in the larynx, and the networks of events remain to be elucidated.
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PMID:Significant involvement of chromosome 13q deletions in progression of larynx cancer, detected by comparative genomic hybridization. 1627 16

A major cause of treatment failure for prostate cancer is the development of androgen-independent metastatic disease. Id protein family, a group of basic helix-loop-helix transcription factors, has been shown to be involved in carcinogenesis and a prognostic marker in several types of human cancers. In this study, we examined the expressions of four Id proteins, Id-1, -2, -3 and -4, in 125 clinical prostate cancer specimens as well as 40 nodular hyperplasia specimens by immunohistochemistry. The expressions of Id proteins were correlated with Gleason grading and metastatic progress of the tumors. We found that Id proteins were dysregulated in prostate cancer. Id-1 and -2 expressions were elevated while Id-3 and -4 expressions were reduced in prostate cancers compared to nodular hyperplasia. Cytoplasmic staining of Id-1 (P=0.013) and nuclear staining of Id-2 (P=0.001) and Id-4 (P<0.001) were positively correlated with Gleason score. The results indicate that these Id proteins may play a positive role in the development of prostate cancer. In contrast, Id-3 might have an inverse relationship with prostate neoplastic transformation (P=0.002) and cancer progression (P=0.022). We found that Id-4 nuclear overexpression in the primary prostate cancers significantly increased the risks to the development of metastasis in the patients (odds ratio=3.215, 95% confidence interval=1.150-8.987, P=0.026). Our results suggest that in prostate cancer patients, differential Id proteins expressions may be a useful marker for poor prognosis, and Id-4 may be a potential prognostic marker for distant metastasis.
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PMID:Id proteins expression in prostate cancer: high-level expression of Id-4 in primary prostate cancer is associated with development of metastases. 1657 99

Melanoma is the most lethal of human skin cancers and its incidence is increasing worldwide [L.K. Dennis (1999). Arch. Dermatol. 135, 275; C. Garbe et al. (2000). Cancer 89, 1269]. Melanomas often metastasize early during the course of the disease and are then highly intractable to current therapeutic regimens [M.F. Demierre and G. Merlino (2004). Curr. Oncol. Rep. 6, 406]. Consequently, understanding the factors that maintain melanocyte homeostasis and prevent their neoplastic transformation into melanoma is of utmost interest from the perspective of therapeutic interdiction. This review will focus on the role of the pocket proteins (PPs), Rb1 (retinoblastoma protein), retinoblastoma-like 1 (Rbl1 also known as p107) and retinoblastoma-like 2 (Rbl2 also known as p130), in melanocyte homeostasis, with particular emphasis on their functions in the cell cycle and the DNA damage repair response. The potential mechanisms of PP deregulation in melanoma and the possibility of PP-independent pathways to melanoma development will also be considered. Finally, the role of the PP family in ultraviolet radiation (UVR)-induced melanoma and the precise contribution that each PP family member makes to melanocyte homeostasis will be discussed in the context of a number of genetically engineered mouse models.
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PMID:Pocket protein function in melanocyte homeostasis and neoplasia. 1682 46

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase linked to the integrin and growth factor receptor-signalling pathways that regulates a number of the biological processes involved in neoplastic transformation, invasion and metastases, such as cell adhesion, migration and apoptosis. Its up-regulation might play a role in the tumourigenesis of invasive tumours, but its involvement in human lung cancer tissues has not yet been determined. We immunohistochemically compared FAK expression and localisation in 60 formalin-fixed and paraffin-embedded non-small cell lung cancer (NSCLC) tissues with that in the surrounding non-neoplastic tissue and in a further five microscopically normal lungs. FAK mRNA levels were quantitatively determined by real-time RT-PCR in frozen tissue specimens of all of the tumours and 21 matched non-neoplastic lung parenchymas, and protein expression in 16 homogenates of the matched neoplastic/non-neoplastic specimens was evaluated by Western blotting. The three different techniques showed that FAK is weakly expressed in non-neoplastic lung parenchyma and up-regulated in NSCLCs. Moreover, Western blotting and real-time RT-PCR indicated a statistically significant correlation between FAK up-regulation and higher disease stages (I+II versus III+IV, p=0.019 and 0.028, respectively). Our results provide evidence that FAK is up-regulated in NSCLCs, and suggest its potential involvement in lung cancer progression.
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PMID:Up-regulation of focal adhesion kinase in non-small cell lung cancer. 1684 83

The Polycomb group (PcG) gene BMI1 is required for the proliferation and self-renewal of normal and leukemic stem cells. Overexpression of Bmi1 oncogene causes neoplastic transformation of lymphocytes and plays essential role in pathogenesis of myeloid leukemia. Another PcG protein, Ezh2, was implicated in metastatic prostate and breast cancers, suggesting that PcG pathway activation is relevant for epithelial malignancies. Whether an oncogenic role of the BMI1 and PcG pathway activation may be extended beyond the leukemia and may affect progression of solid tumors as well remains unknown. Here we demonstrate that activation of the BMI1 oncogene-associated PcG pathway plays an essential role in metastatic prostate cancer, thus mechanistically linking the pathogenesis of leukemia, self-renewal of stem cells, and prostate cancer metastasis. To characterize the functional status of the PcG pathway in metastatic prostate cancer, we utilized advanced cell- and whole animal-imaging technologies, gene and protein expression profiling, stable siRNA-gene targeting, and tissue microarray (TMA) analysis in relevant experimental and clinical settings. We demonstrate that in multiple experimental models of metastatic prostate cancer both BMI1 and Ezh2 genes are amplified and gene amplification is associated with increased expression of corresponding mRNAs and proteins. For the first time, we provide images of human prostate carcinoma metastasis precursor cells isolated from blood and shown to overexpress both BMI1 and Ezh2 oncoproteins. Consistent with the PcG pathway activation hypothesis, increased BMI1 and Ezh2 expression in metastatic cancer cells is associated with elevated levels of H2AubiK119 and H3metK27 histones. Quantitative immunofluorescence colocalization analysis and expression profiling experiments documented increased BMI1 and Ezh2 expression in clinical prostate carcinoma samples and demonstrated that high levels of BMI1 and Ezh2 expression are associated with markedly increased likelihood of therapy failure and disease relapse after radical prostatectomy. Gene-silencing analysis reveals that activation of the PcG pathway is mechanistically linked with highly malignant behavior of human prostate carcinoma cells and is essential for in vivo growth and metastasis of human prostate cancer. We conclude that the results of experimental and clinical analyses indicate the important biological role of the PcG pathway activation in metastatic prostate cancer. Our work suggests that the PcG pathway activation is a common oncogenic event in pathogenesis of metastatic solid tumors and provides justification for development of small molecule inhibitors of the PcG chromatin silencing pathway as a novel therapeutic modality for treatment of metastatic prostate cancer.
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PMID:Essential role for activation of the Polycomb group (PcG) protein chromatin silencing pathway in metastatic prostate cancer. 1696 37

Morbidity and mortality due to prostate cancer are mainly a result of prostate cancer metastases. After the initial neoplastic transformation of cells, the process of metastasis involves a series of sequential steps, which involve neoangiogenesis and lymphangiogenesis, loss of adhesion with migration away from the primary tumour and entry into the systemic vasculature or lymphatics. Metastatic growth in sites such as lymph nodes and bone marrow then involves the specific non-random homing of prostate cancer cells. An appreciation and understanding of this metastatic cascade in relation to prostate cancer is clinically important in order to stratify men with prostate cancer into prognostic groups. Moreover, it is crucial in the future development of therapies that can prevent metastases.
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PMID:The metastatic cascade in prostate cancer. 1715 Mar 54

The role of substance P (SP) in physiological haematopoiesis is well established. However, it also seems to be important in the neoplastic transformation of bone marrow, leading to the development of acute leukaemia in children, and also metastases to bone marrow of solid tumours (particularly neuroblastoma and breast cancer) in early stages of these diseases. This review summarises the available data on SP involvement in both processes. In the future, SP antagonists may be used as anti-neoplastic drugs, for example by direct or indirect blocking of tumour cell proliferation through inhibition of growth factor production and interleukin-1b synthesis.
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PMID:The significance of substance P in physiological and malignant haematopoiesis. 1717 75

Over 90% of all cancers are carcinomas, malignancies derived from cells of epithelial origin. As carcinomas progress, these tumors may lose epithelial morphology and acquire mesenchymal characteristics which contribute to metastatic potential. An epithelial-to-mesenchymal transition (EMT) similar to the process critical for embryonic development is thought to be an important mechanism for promoting cancer invasion and metastasis. Epithelial-to-mesenchymal transitions have been induced in vitro by transient or unregulated activation of receptor tyrosine kinase signaling pathways, oncogene signaling and disruption of homotypic cell adhesion. These cellular models attempt to mimic the complexity of human carcinomas which respond to autocrine and paracrine signals from both the tumor and its microenvironment. Activation of the epidermal growth factor receptor (EGFR) has been implicated in the neoplastic transformation of solid tumors and overexpression of EGFR has been shown to correlate with poor survival. Notably, epithelial tumor cells have been shown to be significantly more sensitive to EGFR inhibitors than tumor cells which have undergone an EMT-like transition and acquired mesenchymal characteristics, including non-small cell lung (NSCLC), head and neck (HN), bladder, colorectal, pancreas and breast carcinomas. EGFR blockade has also been shown to inhibit cellular migration, suggesting a role for EGFR inhibitors in the control of metastasis. The interaction between EGFR and the multiple signaling nodes which regulate EMT suggest that the combination of an EGFR inhibitor and other molecular targeted agents may offer a novel approach to controlling metastasis.
Clin Exp Metastasis 2008
PMID:Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions. 1823 64


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