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)

We report the expression of melanocyte-related genes (MRG) in freshly resected, histopathologically confirmed, human breast cancer specimens and describe experiments illuminating similar observations on a variety of breast cancer cell lines including MDA-MB-435. This finding has implications for research on breast cancer, for clinical investigation of cancer patients presenting with metastases from occult primary tumors and for understanding aberrant differentiation in cancer cells. For example, higher expression of six MRG correlated inversely with propensity for metastatic spread in clones isolated from the human breast cancer cell line MDA-MB-435. Comparisons of MRG expression in cells growing in vitro with those seen in tumors generated by the same lines in vivo showed that the levels of activity of these genes are influenced by the surrounding environment. Also, silencing of expression of the melanocyte-related transcription factor MITF, by transduction of the non-metastatic clone NM2C5 with a construct expressing a specific anti-MITF shRNA, resulted in decreased production of 5 of the melanocyte-related proteins including TYRP1, Pmel 17, MART 1(Melan-A) and TYRP2, but no increase in metastatic capability. Hence MRG expression reproducibly ear-marked, but did not cause, metastatic incompetence. We also report cytogenetic and other data that conflict with the recent suggestion that MDA-MB-435 is of melanocytic origin and are more consistent with its original designation as being of mammary lineage. We conclude that detection of MRG expression profiles in freshly excised breast cancers and in cultured breast cancer cells reflects the operationally important clinical phenomenon of inappropriate gene expression in malignant neoplasms. Concomitantly, we suggest that the evidence we have obtained (i) collectively supports the continued widespread use of the MDA-MB-435 cell line in breast cancer and metastasis research and (ii) advances knowledge of the diversity of aberrant differentiation programs in malignant cells, which is valuable for making accurate diagnoses and treatment decisions in clinical oncology.
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PMID:Expression of melanocyte-related genes in human breast cancer and its implications. 1969 74

Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.
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PMID:Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. 2792 27