Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Normal human cells, cells from nonmalignant proliferative lesions, and primary and metastatic tumor cells can be maintained in vitro and analyzed for requirements for growth in chemically defined media. The human melanocytic cell system with normal melanocytes, precursor nevus cells, and primary and metastatic melanoma cells has been extensively studied for the phenotypic properties of the cells, including their requirements for exogenous growth factors and other mitogens. In high calcium-containing W489 medium, normal melanocytes require four supplements: IGF-I (or insulin); bFGF, TPA, and alpha-MSH. Nevus cells are largely independent of bFGF. Depletion of TPA from medium is not as detrimental to nevus cells as it is to melanocytes, but the phorbol ester is still essential for maintenance of the typical nevic phenotype. Primary melanoma cells require at least one growth factor, IGF-I (or insulin), for continuous proliferation. On the other hand, metastatic cells of melanoma as well as of carcinomas of colon and rectum, bladder, ovary, and cervix are able to proliferate after a short adaptation period in medium depleted of any growth factors and other proteins. Doubling times of metastatic tumor cells in protein-free medium are only 30-60% longer than in FCS-containing medium. The growth autonomy of human tumor cells is apparently due to the endogenous production of growth factors. Likely candidates for autocrine growth stimulation of human tumor cells are TGF-alpha, TGF-beta, and PDGF. Melanoma and colorectal carcinoma cells express functional EGF/TGF-alpha receptors, and produce TGF-alpha, indicating that this growth factor is produced for autocrine stimulation. In addition to the use of anti-growth factor antibodies, other strategies for the inhibition of autocrine growth stimulation include mAbs to growth factor receptors, soluble receptors, receptor-mimicking antiidiotype antibodies, and active immunization against growth factors. Whether any of these therapeutic approaches is clinically feasible will need to be determined in extensive preclinical investigations.
 ...
PMID:Growth-regulatory factors for normal, premalignant, and malignant human cells in vitro. 240 78

Fibroblast growth factors (FGFs) strongly bind to heparin and are thereby stabilized against deactivation and proteolytic cleavage. Sucrose octasulfate (SOS), which has a chemical structure resembling the repeating unit of heparin, has also been shown to enhance stability of basic FGF against thermal denaturation and to induce a small conformational change. We have examined SOS binding to bFGF using equilibrium dialysis. The difference in SOS concentration across the dialysis membrane was measured using a precision density meter, since the density of SOS differs greatly from that of water. With care, this densimetric technique can measure binding with a precision of +/- 0.1 mol/mol using about 2 mg/ml of protein. These results show that the binding saturates at 2 mol of SOS per mole of bFGF as the SOS concentration increases to 3.6 mM or higher. The effect of SOS on the thermal stability of bFGF was examined using denaturation at a constant heating rate, by both turbidity and differential scanning calorimetry. Since the thermal denaturation is irreversible, the temperature where aggregation abruptly increases was taken to indicate the onset of denaturation. This temperature increased by approximately 12 degrees C as the SOS concentration increased from 0.018 to 3.6 mM and remained constant above 3.6 mM, consistent with our binding data if the binding is specific to the native state.
 ...
PMID:Densimetric determination of equilibrium binding of sucrose octasulfate with basic fibroblast growth factor. 813 19

Basic fibroblast growth factor (bFGF or FGF-2) is produced by nearly all melanomas in vitro and in vivo but not by normal melanocytes, which require exogenous bFGF for growth. In this study, we transduced normal human melanocytes to overexpress two forms of bFGF: (bFGF-Long and bFGF-Short) using replication-deficient adenovirus 5 vectors. bFGF-Long induced the 17.8, 22.5, 23.1 and 24.2 kDa forms of bFGF, whereas bFGF-Short induced only the 17.8 kDa mature form. Growth of cultured melanocytes transduced with either vector was similar to that of nevus and melanoma cells and was independent of exogenous bFGF and of insulin/insulin-like growth factor 1, and cyclic AMP enhancers, requiring only phorbol ester as an exogenous mitogen. Like primary melanoma cells, transduced normal melanocytes grew anchorage independently in soft agar. When injected into the dermis of human skin grafted to mice, bFGF-transduced melanocytes proliferated for at least 20 days, whereas cells from control cultures showed poor survival and no proliferation. These results demonstrate that bFGF upregulation is a critical component in melanoma progression.
 ...
PMID:Basic fibroblast growth factor induces a transformed phenotype in normal human melanocytes. 1059 49

Factors regulating transcription of pluripotency genes in congenital nevo-melanocytes are not known. Nevo-melanocytes belong somewhere in-between the ends of a spectrum where the normal epidermal melanocyte represents one end and a melanoma cell with multiple genetic abnormalities represents the other. Cells from large/giant congenital nevi (L/GCMN), unlike normal melanocytes, grow colonies on soft agar and express pluripotency markers, similar to melanoma cells. In this study normal melanocytes, SKMEL28 melanoma cells and nevo-melanocytes isolated from three L/GCMN patients were exposed to niche factors bFGF and IGF1 in vitro at physiological doses, and expression of a panel of pluripotency markers was determined by RT-PCR. While normal melanocytes did not show any significant transcriptional change in the genes studied, bFGF induced transcription of Sox2 and Bmi1 in melanoma cells. Patients' cells showed differential expression, with Sox10 being common to C76N and PD1N, while only Sox2 and Bmi1 were upregulated in C139N. IGF1 on the other hand induced unique sets of genes in each individual sample. We conclude that expression of pluripotency genes in L/GCMN cells is affected by niche factors bFGF and IGF1; however, each individual growth factor induced a unique set of genes in a patient's cells.
 ...
PMID:Pluripotency markers are differentially induced by IGF1 and bFGF in cells from patients' lesions of large/giant congenital melanocytic nevi. 3067 61