Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The possible mitogenic activity of fibronectin (FN) in human primary and metastatic melanoma lines and clones and the involvement of integrins in mediating this effect were evaluated. Quescent human melanoma cells cultured in serum-free medium proliferated in a dose- and time-dependent fashion to immobilized FN as indicated by [3H]thymidine incorporation, increment of cell number, and cell cycle analysis. This response to FN was observed with tumor clones isolated from a subcutaneous metastasis and with primary or metastatic melanomas from different patients, but only when tumor cells expressed the alpha 5 subunit of the FN receptor (i.e., VLA-5). Proliferation to FN by a primary tumor (Me4405) expressing all FN receptors and by a tumor clone (2/60) lacking only the alpha 4 subunit was inhibited by monoclonal antibodies to the alpha 5 and beta 1 but not by monoclonal antibodies to other subunits of FN receptors. Mapping of FN regions responsible for the proliferative signal was performed by stimulating melanoma cells with different FN proteolytic fragments and indicated that a significant mitogenic signal was provided by the M(r) 120,000 alpha-chymotrypsin fragment containing the Arg-Gly-Asp sequence. The proliferation of melanoma cells to FN and to FN fragments was also significantly inhibited by peptides containing the Arg-Gly-Asp sequence. These data indicate that FN can stimulate the proliferation of quiescent melanoma cells and that integrins as alpha 5 beta 1 are involved in the response of tumor cells to this extracellular matrix protein.
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PMID:Role of the alpha 5 beta 1 integrin receptor in the proliferative response of quiescent human melanoma cells to fibronectin. 138 57

We have investigated the anti-angiogenic effect of a polymeric peptide based on the Arg-Gly-Asp (RGD) core sequence of fibronectin as a monomer unit, i.e., poly(RGD), in syngeneic mice and in vitro. Single intratumoral administration of poly(RGD) on day 0, 1 or 7 after tumor implantation achieved a significant reduction of B16-BL6 melanoma colonization in the lungs, but did not affect the size of the primary tumor at the time of amputation. The number of capillary blood vessels oriented toward the tumor mass increased during the early growth phase after the intradermal inoculation of the tumor. Poly(RGD) significantly inhibited the formation of tumor neovascularization when co-injected with the tumor cells or separately injected intratumorally or intravenously on day 1 or 3 after tumor inoculation. This inhibitory effect of poly(RGD) was dose-dependent. Poly(RGD) was able to inhibit the haptotactic migration of endothelial cells along a gradient of substratum-immobilized fibronectin but not laminin. Tumor-conditioned medium (CM) by itself did not act as a chemoattractant when it was added in the lower compartment of a Transwell chamber, but promoted the endothelial cell migration to immobilized fibronectin or laminin. Poly(RGD) inhibited the enhanced cell migration to fibronectin but not to laminin in response to CM. Thus, poly(RGD)-mediated inhibition of tumor metastasis may be partly due to the inhibition of tumor-induced angiogenesis at primary and secondary sites.
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PMID:Inhibition of tumor angiogenesis by a synthetic cell-adhesive polypeptide containing the Arg-Gly-Asp (RGD) sequence of fibronectin, poly(RGD). 169 94

We have investigated the anti-metastatic and anti-invasive activities of polypeptide analogues based on the Arg-Gly-Asp (RGD) adhesive signal in fibronectin, poly(RGD), poly(RGDS)[Arg-Gly-Asp-Ser] and poly(RGDT)[Arg-Gly-Asp-Thr]. These polypeptides containing repetitive RGD sequences were able to inhibit experimental and spontaneous lung metastases of B16-BL6 cells more effectively than the corresponding monomer peptides. In the spontaneous metastasis model, multiple i.v. administrations of these polymeric peptides before or after surgical excision of the primary tumor resulted in a significant reduction of lung tumor colonies. However, there was no significant difference in ability to inhibit spontaneous lung metastasis among poly(RGD), poly(RGDS) and poly(RGDT), although the carboxy-terminal amino acid residue (i.e., Xaa in -RGDXaa-) has been shown to play an important role in the expression of cell adhesive character. The treatment with poly(RGD) substantially prolonged the survival time for mice injected s.c. with B16-BL6 melanoma as compared with the untreated control. We also found that the polypeptides were potently able to inhibit the invasion and migration of tumor cells in vitro. Since these polypeptide analogues showed no antigenicity in the host and had no toxic effect on tumor cells in vitro, they may be potentially useful in the prevention of cancer metastasis.
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PMID:Anti-metastatic and anti-invasive effects of polymeric Arg-Gly-Asp (RGD) peptide, poly(RGD), and its analogues. 211 67

We investigated that the antimetastatic and antiadhesive activities of peptides based on Arg-Gly-Asp adhesive signal in fibronectin could be augmented by their polymerization. Poly(Arg-Gly-Asp), which consists of a repetitive sequence of Arg-Gly-Asp, inhibited lung metastases in C57BL/6 mice more effectively than Arg-Gly-Asp tripeptide was able to do, when coinjected or separately injected with B16-BL6 cells. The adhesion of tumor cells to fibronectin was specifically inhibited by adding poly(Arg-Gly-Asp) but not unrelated peptides. In contrast, poly(Arg, Gly, Asp), in which three amino acids are randomly arranged, showed neither inhibition of lung metastases nor any adhesive ability to attach to tumor cells. The inhibitory effect of polymeric peptides containing the Arg-Gly-Asp sequence on lung metastases decreased according to the decreasing repeat units of the Arg-Gly-Asp core sequence. Polymeric peptides with Arg-Gly-Asp entrapped within the liposome membranes also caused a remarkable reduction of metastatic colonies. In a spontaneous metastasis model, multiple i.v. administrations of poly(Arg-Gly-Asp) after tumor inoculation caused the significant reduction of metastatic colonies in the lung but did not affect the growth (size) of primary tumor. We found that the polymerization (multivalency) of the Arg-Gly-Asp core sequence was able to augment the inhibition of tumor lung metastases in experimental and spontaneous metastasis models as well as the cell-adhesive property more effectively than a monovalent unit of Arg-Gly-Asp peptide.
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PMID:Inhibition of the metastasis of murine malignant melanoma by synthetic polymeric peptides containing core sequences of cell-adhesive molecules. 273 23

Since the adhesive interaction between tumor cells and host cells, or extracellular matrix (ECM), presumably plays a crucial role in metastatic formation, we used synthetic or recombinant polypeptide analogues, poly (RGD), CH-271 or SCM-chitin-RGDS based on Arg-Gly-Asp (RGD) sequence. Poly (RGD) effectively inhibited the experimental lung and liver metastasis when coinjected i.v. with different types of tumors. In a spontaneous lung metastasis model using B16-BL6 melanoma, multiple administrations of this polypeptide, before or after surgical excision of the primary tumor, resulted in significant inhibition of tumor metastasis. The mechanism responsible for the inhibition is partly associated with the ability to interfere with cell functions such as adhesiveness, motility, and invasiveness in the process of metastasis. CH-271 fusion polypeptide was much more effective in inhibiting lung or liver metastasis of tumors than cell-binding domain (C-274) or heparin-binding domain (H-271) polypeptides. SCM-chitin-RGDS conjugate significantly reduced the number of tumor colonies in the lungs by coinjection with Colon 26 carcinoma as compared with either RGDS or SCM-chitin alone. Since the polypeptides derived from cell adhesion molecules showed no toxicity to the host, they may provide a promising approach for the control of cancer metastasis.
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PMID:[Inhibition of tumor metastasis by synthetic peptide analogues of cell-adhesive RGD sequence of fibronectin]. 763 3

We have investigated the inhibitory effect of the N-terminal modified Arg-Gly-Asp-Ser (RGDS) analogues, AcDRGDS and AcDRLDS, on tumor cell adhesion to the components of extracellular matrix and basement membrane, and also tested the antimetastatic effect of their conjugates with trimesic acid, Ar(DRGDS)3 and Ar(DRLDS)3. AcDRGDS significantly inhibited tumor cell adhesion to fibronectin, vitronectin and RGDS substrates, but not to CS1 substrate which is a ligand for the alpha 4 beta 1 tumor surface integrin receptor. In contrast, AcDRLDS variant peptide significantly inhibited tumor cell adhesion to laminin, in addition to RGDS-mediated adhesion to fibronectin and vitronectin. AcDRLDS also inhibited tumor cell adhesion to CS1 as well as the RGDS sequence within the fibronectin molecule in a concentration-dependent manner, although the inhibitory effect was less than that of the CS1 (EILDV) peptide. Ar(DRLDS)3 inhibited the laminin- and fibronectin-mediated invasion and migration of tumor cells, whereas Ar(DRGDS)3 selectively inhibited fibronectin-mediated invasion and migration. Ar(DRGDS)3 and Ar(DRLDS)3 were much more effective in inhibiting experimental lung or liver metastases of various types of murine and human tumors than the original RGDS-containing peptides or Ar(COONa)3. Multiple administrations of Ar(DRGDS)3 or Ar(DRLDS)3 potently inhibited spontaneous lung metastasis produced by intra-footpad injection of B16-BL6 cells without affecting the primary tumor size at the time of surgical excision, as compared with RGDS peptide or untreated control. Thus, Ar(DRGDS)3 and Ar(DRLDS)3 substantially increased the exhibiting any antimetastatic effect of the peptides without direct cytotoxicity.
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PMID:Antimetastatic activities of synthetic Arg-Gly-Asp-Ser (RGDS) and Arg-Leu-Asp-Ser (RLDS) peptide analogues and their inhibitory mechanisms. 878 88

Since the adhesive interaction between tumor cells and host cells, or extracellular matrix (ECM), presumably plays a crucial role in metastatic formation during a series of complex events, we used synthetic or recombinant polypeptide analogues, poly(RGD) or CH-271-based on Arg-Gly-Asp(RGD) sequence or functional domains in fibronectin. Use of these analogues regulated the mechanisms involved in cell adhesion during the metastatic process. Poly(RGD) effectively inhibited the experimental lung and liver metastasis when coinjected i.v. with different types of tumors. In a spontaneous lung metastasis model using B-16-BL6 melanoma, multiple administrations of this polypeptide, before or after surgical excision of the primary tumor, resulted in significant inhibition of tumor metastasis without affecting the growth of the primary tumor. Further, it substantially prolonged the survival time of mice. The mechanism responsible for the inhibition of tumor metastasis by the polypeptides is partly associated with the ability to interfere with cell functions such as adhesiveness, motility, and invasiveness in the cellular adhesive process of metastasis. The combination of CH-271 fusion polypeptide and anticancer drugs, i.e., anti-adhesion therapy and chemotherapy, caused a dramatic inhibition of lung and liver metastasis of tumors when compared with either treatment alone, or in the control. Since the polypeptides derived from cell adhesion molecules showed no short-term toxicity to the host, they may provide a promising approach for the control of cancer metastasis.
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PMID:Prevention of cancer metastasis in mice with fibronectin-related substances. 898 70

Thyroid carcinomas, even when well differentiated, usually appear as hypofunctioning at scintigraphy. We report a case of an aggressive insular thyroid carcinoma presenting as an autonomously functioning thyroid nodule and causing severe thyrotoxicosis. The tumor was metastatic to a cervical lymph node and both lungs. An activating mutation of the TSH receptor gene in both the primary tumor and the lymph node metastasis was found, due to a base substitution at codon 633 (normal guanine at position 1896 replaced by cytosine CAC for GAC causing aspartic acid substitution by histidine). Other known oncogenes (gsp, ras, PTC/ret, trk, met, and p53) were not involved. This is the first description of an activating TSH receptor mutation in a thyroid hyperfunctioning carcinoma in which an aggressive malignant phenotype coexisted with activation of the cAMP cascade and differentiated thyroid functions.
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PMID:Detection of an activating mutation of the thyrotropin receptor in a case of an autonomously hyperfunctioning thyroid insular carcinoma. 936 May 62

The adhesive interaction between tumor cells and host cells or the extracellular matrix plays a crucial role in metastasis formation. Therefore, understanding the mechanism controlling metastasis may assist in the development of antimetastatic therapy. We have used synthetic or recombinant polypeptide analogues containing the Arg-Gly-Asp (RGD) sequence found in the functional domains of fibronectin, such as poly(RGD) or CH-271, to regulate the mechanisms involved in cell adhesion during the metastatic process. Poly(RGD) inhibited experimental lung and liver metastasis effectively when coinjected i.v. with various types of tumors. In a model of spontaneous lung metastasis using the B16-BL6 melanoma, repeated administration of this polypeptide before or after surgical excision of the primary tumor resulted in a significant inhibition of tumor metastasis without affecting the growth of the primary tumor and substantially prolonged the survival time of mice. The mechanism responsible for the inhibition of tumor metastasis by the polypeptides is at least partly associated with the ability to interfere with cellular functions such as adhesiveness, motility and invasiveness in the process of metastasis. Combined treatment of the CH-271 fusion polypeptide and anticancer drugs, i.e., anti-adhesion therapy combined with chemotherapy, caused a marked inhibition of lung and liver metastasis of tumors as compared with either treatment alone or with the control. In contrast, the promotion of tumor cell interaction with immune cells via cell adhesion molecules, which differs from the anti-adhesive mechanism, may lead to the induction of anti-tumor immune responses and, consequently, to the inhibition of tumor metastasis. The transfection of the gene of the B7-1 adhesion molecule into tumor cells (B16-BL6 or K1735-M2 melanoma) resulted in the remarkable reduction of lung metastasis caused by the i.v. injection into mice. Immunization of B7-transfected tumor was effective as a tumor vaccine for preventing the metastasis of B7 negative original tumor cells. Thus, the regulation of the adhesive interaction with tumor cells may provide a new and promising approach for the control and prevention of cancer metastasis.
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PMID:Cell adhesion molecules and cancer metastasis. 943 54

One of the principle targets for metastasis of follicular thyroid carcinoma (FTC) is the skeleton. Because no data are available on the role of the integrin adhesion molecule family in the attachment of FTC to bone, we studied the attachment characteristics of three FTC cell lines to bone and the role of integrins. Three cell lines were used from the same patient, one (FTC-133) from the primary tumor and two (FTC-236 and FTC-238) from metastases. Attachment of FTC cell lines to bone was assessed on conditioned medium of an osteoblastic cell line, coated onto plastic, as an in vitro model of bone matrix. The synthetic RGD (Arg-Gly-Asp) peptide GRGDS impaired attachment of the FTC cell lines to bone matrix, demonstrating the role of integrins in the attachment of FTC to bone. Attachment of FTC-133 to bone matrix was blocked completely by GRGDS, whereas attachment of FTC-236 and FTC-238 could not be impaired completely. Semiquantitative polymerase chain reaction (PCR) of cDNA from the cell lines indicated stronger expression of alpha5 integrin mRNA in FTC-133 than in the other cell lines. In line with this, attachment of FTC-133 to bone matrix could be inhibited almost completely by anti alpha5 and beta1 integrin antibodies, indicating the importance of the fibronectin receptor in the attachment of FTC-133 to bone. Binding of FTC-236 and FTC-238 to bone matrix could not be inhibited completely by anti-integrin antibodies, suggesting an additional role of nonintegrin adhesion molecules in the attachment of FTC-236 and FTC-238 to bone. The synthetic bone sialoprotein cyclic peptide, CNB, revealed antiadhesive effects in the binding of FTC to bone. In conclusion, integrins play an important role in the attachment of metastatic FTC to bone. Differences in the functional involvement of integrins in the attachment to bone are observed between the three cell lines studied. From the present results, antiadhesive interventions with synthetic RGD peptides in FTC may be designed.
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PMID:Role of integrins in the attachment of metastatic follicular thyroid carcinoma cell lines to bone. 949 50


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