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)

Conditioned media from fetal rat calvarial cultures has previously been shown to stimulate the growth of the bone-metastasizing Walker 256 carcinosarcoma cell line. In the current investigation we looked at the possibility that transforming growth factor-beta (TGF-beta), present in conditioned media, and positively correlated with resorption in vitro, may be responsible for the enhanced proliferation of Walker cells cultured in these conditioned media. Purified platelet-derived TGF-beta produced a dose-dependent growth response in Walker cells with an ED50 equal to 0.05 ng/ml. Bone-derived TGF-beta activity in conditioned media, measured by NRK fibroblast colony formation, correlated well with percentage resorption in bone cultures, and growth activity in Walker cell culture. In addition to this, the growth response normally seen with conditioned media cultures of Walker cells was significantly inhibited by the addition of anti-TGF-beta 1 neutralizing antibody. We conclude that TGF-beta is an important growth stimulatory component from fetal rat calvaria.
Clin Exp Metastasis
PMID:In vitro effects of bone- and platelet-derived transforming growth factor-beta on the growth of Walker 256 carcinosarcoma cells. 222 66

Bone is a major source of transforming growth factor-beta (TGF-beta), and a preferred target organ for metastasis of the rat Walker carcinosarcoma 256 (W256). Since chemotactic mechanisms may contribute to metastatic site specificity, we have tested the hypothesis that TGF-beta is a chemoattractant for these cancer cells. Purified platelet-derived TGF-beta elicited dose-dependent migration of W256 cells in the Boyden chamber assay with half-maximal responses (ED50) elicited by 0.12 +/- 0.01 ng TGF-beta/ml. Checkerboard analysis confirmed dependence of the response upon a concentration gradient. Conditioned media from organ cultures of bone contained TGF-beta and chemotactic activity in proportion to the extent of bone resorption. The chemotactic activity in conditioned bone culture medium and that of the purified platelet-derived TGF-beta were both inhibited after incubation with anti-TGF-beta 1. We conclude that TGF-beta, released from resorbing bone, can influence the migratory behavior of the osteotropic W256 cell line.
Invasion Metastasis 1990
PMID:Chemotactic activity of bone and platelet-derived TGF-beta for bone-metastasizing rat Walker 256 carcinosarcoma cells. 235 28

Metastasis in children with neuroblastoma (NB) is a poor prognostic factor despite intensive therapy. In the near future, stem cell factor (SCF) is likely to be used clinically to accelerate bone marrow (BM) recovery after high-dose chemotherapy in patients with advanced NB. The high frequency of BM metastases in NB could be secondary to BM-derived human growth factors (HGF) modulating the adhesion, secondary growth (or both) of circulating metastatic NB cells. To test this hypothesis, we studied the in vitro effects on NB cell lines grown in chemically defined medium of SCF, interleukin (IL)-1 beta, IL-3, IL-6, basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-beta) used alone or in combination. The antigenic expression of NB-associated cell adhesion molecules (CAM) HLA class 1, intercellular CAM-1, neural-CAM and CD44 were assayed by monoclonal antibodies and flow cytometry, and DNA synthesis by 3H-thymidine uptake. The expression of CAM was not modulated by SCF or other HGFs. An increase in thymidine uptake was induced by bFGF alone in IMR-32 cells, while SCF and other HGFs had no notable effect. Our results indicate that SCF and other BM-derived HGFs are unlikely to have a generalised effect on the expression of adhesion molecules by NB cells or proliferation. The clinical administration of recombinant human SCF to children with NB should be safe.
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PMID:Effects of stem cell factor and other bone marrow-derived growth factors on the expression of adhesion molecules and proliferation of human neuroblastoma cells. 757 47

To determine the biological role of transforming growth factor-beta (TGF-beta) in mammary carcinomas in vivo, estrogen-dependent MCF-7 cells were transfected with a mouse TGF-beta 1 cDNA. Growth characteristics in culture were not altered in the transfected cells. However, the MCF-7/TGF-beta 1 cells formed tumors in ovariectomized athymic mice in the absence of estrogen supplementation. Daily injections of human recombinant TGF-beta 1 supported tumor formation by wild-type MCF-7 cells in castrated nude mice in the absence of exogenous estradiol. In another approach to the same question, the effect of anti-TGF-beta antibodies on tumor formation by estrogen-independent MDA-231 cells was examined. The 2G7 IgG2b (2G7) antibody, which neutralizes TGF-beta 1, -beta 2, and -beta 3, blocked the formation of MDA-231 tumors at the injection site and lung metastases in nude mice. Inoculation of MDA-231 cells inhibited, while injection of 2G7 increased mouse spleen natural killer (NK) activity. 2G7 did not inhibit MDA-231 tumors and metastases in NK-deficient animals. Finally, medium conditioned by MDA-231 cells inhibited lymphocyte-mediated NK activity; this inhibition was abrogated by 2G7, but not by a control IgG2. These data support a positive role for tumor cell TGF-beta in the maintenance and/or progression of mammary carcinoma cells in an intact host.
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PMID:Evidence for a positive role of transforming growth factor-beta in human breast cancer cell tumorigenesis. 800 96

Prostate tumor cells preferentially metastasize to bony sites and lymph nodes at a frequency in excess of that which would be predicted by random tumor cell dissemination. In order to determine whether chemoattractants in these organs promote organ-specific metastasis, we utilized human cell lines derived from and/or related to these organs as sources of potential chemoattractants. Secretory proteins derived from the cell lines MG-63 (osteosarcoma), SK-ES-1 (Ewing's sarcoma), and KG-1 (leukemia) stimulated chemomigration of the TSU-pr1 prostate tumor cells in a dose-dependent manner in Boyden chambers. In addition, secretory proteins from a human prostatic stromal cell line (hPS) and from the TSU-Pr1 prostate tumor cell line were also able to stimulate chemomigration of the TSU-pr1 cells through Boyden chambers. Since lymph nodes and bony sites represent organs of hematopoietic/lymphoid proliferation and activation, we undertook identification of specific cytokines present at these sites which may promote the chemomigration of prostate tumor cells. In this context, the cytokines interleukin-1 alpha, interleukin-2, interleukin-6, tumor necrosis factor-beta, transforming growth factor-beta, interferon alpha 2-a, and granulocyte-macrophage colony-stimulating factor did not stimulate chemomigration of the TSU-pr1 prostate tumor cell line. In contrast, the cytokine epidermal growth factor (EGF) stimulated chemomigration of the TSU-pr1 prostate tumor cells through the Boyden chambers in a dose-dependent manner. Western blot analysis of secretory proteins from the cell lines KG-1, SK-ES-1, MG-63, hPS, and TSU-pr1 identified EGF-immunoreactive proteins in all cases. In addition, EGF immunoreactivity was localized to the stroma of the human prostate, the osteogenic stroma of pelvic medullary bone, and the stroma within the capsule and trabeculae of pelvic lymph nodes. Hence, these results demonstrate that the cytokine EGF promotes the chemomigration of the TSU-pr1 prostate tumor cell line, and that EGF within the stroma of pelvic lymph nodes and medullary bone may act as a chemoattractant for prostate tumor cells, thereby facilitating the preferential formation of metastatic foci within these organs.
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PMID:Epidermal growth factor (EGF) promotes chemomigration of a human prostate tumor cell line, and EGF immunoreactive proteins are present at sites of metastasis in the stroma of lymph nodes and medullary bone. 854 75

Many studies show defective immune responses in patients diagnosed with cancer. Most of the diverse nonspecific approaches used to stimulate the immune system to recognize and destroy abnormal tumor cells have limited clinical utility. Attempts to identify tumor-specific antigens and to improve the antigen presentation were equally disappointing. It appears that some of these failures can be explained by tumor-induced immunosuppression. A large number of cytokines, hormones, and other molecules secreted by tumors were demonstrated to have immunomodulating properties. The most extensively studied immunosuppressive molecules secreted by tumors are transforming growth factor-beta (TGF beta), interleukin 10 (IL-10), and prostaglandin E2 (PGE2). TGF beta in particular may play a key role in tumor-induced immunosuppression. It is the most potent immunosuppressor described to date, and it has been consistently isolated from variety of tumor cell lines and detected in plasma of tumor-bearing hosts. Level of TGF beta production by tumor cells correlates with their metastatic potential, and TGF beta neutralization not only prevents development of metastases, but also inhibits growth or completely eradicates tumors as diverse as breast cancer, melanoma, and malignant gliosarcoma in animal models. PGE2 may play significant role in early stages of tumor development, promoting the process of tumorigenesis in some tumors. Research on reversal of tumor-induced immunosuppression promises new, more powerful, and less toxic approaches to cancer therapy. Existence of molecule(s) consistently secreted by different types of tumors and responsible for tumor progression raises the possibility of a single, universal assay to monitor progression and recurrence in many malignancies, including those that currently do not have reliable plasma markers.
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PMID:Reversal of tumor-induced immunosuppression: a new approach to cancer therapy. 918 55

Squamous cell carcinomas (SCCs) of the head and neck are malignant tumors with high capacity to invade and metastasize. We have examined expression of the new collagenase, collagenase-3 (MMP-13), in SCCs of the head and neck. MMP-13 mRNAs were detected in 22 of 29 SCC cell lines: in 14 of 15 primary SCC cell lines and in 8 of 14 SCC cell lines from recurrent tumors or metastases. MMP-13 mRNAs were expressed by all 6 cell lines from highly invasive primary tumors and in all 4 cell lines from small aggressive tumors. Using in situ hybridization, MMP-13 mRNAs were detected in 15 of 17 SCC tumor samples. In most tumors, MMP-13 was expressed by tumor cells at the invading front of the tumors, but in a subset of SCCs, MMP-13 mRNA was also expressed by stromal fibroblasts. No MMP-13 expression was detected in intact skin or oral mucosa. MMP-13 mRNA levels in SCC cells were enhanced by transforming growth factor-beta, tumor necrosis factor-alpha, transforming growth factor-alpha, and keratinocyte growth factor. Specific expression of MMP-13 by SCC cells in vitro and in vivo strongly suggests a role for MMP-13 in the high invasion capacity of SCC cells.
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PMID:Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck. 925 Jan 62

Solid cancers metastasize to bone by a multistep process that involves interactions between tumor cells and normal host cells. Some tumors, most notably breast and prostate carcinomas, grow avidly in bone because the bone microenvironment provides a favorable soil. In the case of breast carcinoma, the final step in bone metastasis (namely bone destruction) is mediated by osteoclasts that are stimulated by local production of the tumor peptide parathyroid hormone-related peptide (PTH-rP), whereas prostate carcinomas stimulate osteoblasts to make new bone. Production of PTH-rP by breast carcinoma cells in bone is enhanced by growth factors produced as a consequence of normal bone remodeling, particularly activated transforming growth factor-beta (TGF-beta). Thus, a vicious cycle exists in bone between production by the tumor cells of mediators such as PTH-rP and subsequent production by bone of growth factors such as TGF-beta, which enhance PTH-rP production. The metastatic process can be interrupted either by neutralization of PTH-rP or by rendering the tumor cells unresponsive to TGF-beta, both of which can be accomplished experimentally. The osteoclast is another available site for therapeutic intervention in the bone metastatic process. Osteoclasts can be inhibited by drugs such as the new-generation bisphosphonates; as a consequence of this inhibition, there is a marked reduction in the skeletal events associated with metastatic cancer to bone, such as pain, fracture, and hypercalcemia. However and possibly even more importantly, there is also a reduction of tumor burden in bone. In experimental situations, this has clearly been shown to affect not only morbidity but also survival. The precise mechanism by which bisphosphonates inhibit osteoclasts is still unclear and may represent a combination of inhibition of osteoclast formation as well as increased apoptosis in mature osteoclasts. However, studies with potent bisphosphonates such as ibandronate, pamidronate, and risedronate have clearly documented that reduction of bone turnover and osteoclast activity leads to beneficial effects not only on skeletal complications associated with metastatic cancer, but also on tumor burden in bone.
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PMID:Mechanisms of bone metastasis. 936 21

Parathyroid hormone-related protein (PTH-rP) was purified and cloned 10 years ago as a factor responsible for the hypercalcemia associated with malignancy. Clinical evidence supports another important role for PTH-rP in malignancy as a mediator of the bone destruction associated with osteolytic metastasis. Patients with PTH-rP positive breast carcinoma are more likely to develop bone metastasis. In addition, breast carcinoma metastatic to bone expresses PTH-rP in >90% of cases, compared with only 17% of metastasis to nonbone sites. These observations suggest that PTH-rP expression by breast carcinoma cells may provide a selective growth advantage in bone due to its ability to stimulate osteoclastic bone resorption. Furthermore, growth factors such as transforming growth factor-beta (TGF-beta), which are abundant in bone matrix, are released and activated by osteoclastic bone resorption and may enhance PTH-rP expression and tumor cell growth. To investigate the role of PTH-rP in the pathophysiology of breast carcinoma metastasis to bone, the human breast carcinoma cell line MDA-MB-231 was studied in a murine model of human breast carcinoma metastasis to bone. A series of experiments were performed in which 1) PTH-rP secretion was altered, 2) the effects of PTH-rP were neutralized, or 3) the responsiveness to TGF-beta was abolished in MDA-MB-231 cells. Cultured MDA-MB-231 cells secreted low amounts of PTH-rP that increased fivefold in response to TGF-beta. Tumor cells inoculated into the left cardiac ventricle of nude mice caused osteolytic metastasis similar to that observed in humans with breast carcinoma. When PTH-rP was overexpressed in the tumor cells, bone metastases were increased. MDA-MB-231 cells transfected with the cDNA for human preproPTH-rP secreted a tenfold greater amount of PTH-rP and caused significantly greater bone metastases when inoculated into the left cardiac ventricle of female nude mice compared with parental cells. In contrast, when the biologic effects of PTH-rP were neutralized or its production was suppressed, such metastases were decreased. Treatment of mice with a neutralizing monoclonal antibody to human PTH-rP resulted in a decrease in the development and progression of bone metastasis due to the parental MDA-MB-231 cells. Similar results were observed when mice were treated with dexamethasone, a potent glucocorticoid that suppresses production of PTH-rP by the MDA-MB-231 cells in vitro. The role of bone-derived TGF-beta in the development and progression of bone metastasis was studied by transfecting MDA-MB-231 cells with a cDNA encoding a TGF-beta type II receptor lacking a cytoplasmic domain, which acts as a dominant negative to block the cellular response to TGF-beta. Stable clones expressing this mutant receptor (MDA/TbetaRIIdeltacyt) did not increase PTH-rP secretion in response to TGF-beta stimulation compared with controls of untransfected MDA-MB-231 or those transfected with the empty vector. Mice inoculated into the left cardiac ventricle with MDA/TbetaRIIdeltacyt had fewer and smaller bone metastases as assessed radiographically and histomorphometrically compared with controls. Taken together, these data suggest that PTH-rP expression by breast carcinoma cells enhance the development and progression of breast carcinoma metastasis to bone. Furthermore, TGF-beta responsiveness of breast carcinoma cells may be important for the expression of PTH-rP in bone and the development of osteolytic bone metastasis in vivo. These interactions define a critical feedback loop between breast carcinoma cells and the bone microenvironment that may be responsible for the alacrity with which breast carcinoma grows in bone.
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PMID:Parathyroid hormone-related protein and bone metastases. 936 24

Although several neoplasms may produce osteoblastic metastases, carcinoma of the prostate is by far the most common. Biochemical and histologic studies indicate that osteolysis also is a manifestation of prostate carcinoma. Furthermore, factors such as parathyroid hormone-related peptide, which mediate osteolysis in other cancers, also appear to be operative in the bone breakdown induced by prostate carcinoma. However, the most unique skeletal effect of this tumor is its consistent capacity to stimulate osteoblasts to deposit new bone. Several bone growth factors have been detected in prostatic tissue and may contribute to this process. These include transforming growth factor-beta, fibroblast growth factor, and bone morphogenetic proteins. The author isolated an amino-terminal fragment (ATF) of the protease urokinase (uPA) from the conditioned medium of the prostate carcinoma cell line PC-3 and demonstrated that this fragment has mitogenic activity for osteoblastic cells. The activity appears to reside in an epidermal growth factor-like growth factor domain (GFD) within the ATF. Subsequently, the author cloned the rat uPA receptor (uPAR). uPAR is known to bind the ATF and can permit the uPA molecule to exhibit focal proteolysis. It was shown that the ATF also can induce c-myc, c-jun, and c-fos in osteoblastic cells. This effect of ATF can be mimicked by the GFD and suggests that this signalling pathway in osteoblasts is via the uPAR. Consequently, the uPA molecule may contribute to growth factor effects in osteoblasts via the NH2-terminal fragment and to tumor invasiveness via its COOH-terminal proteolytic domain. This scenario is supported by results from studies with uPA-overexpressing prostate carcinoma cells in rats. Additional studies will be required to further define the mechanisms of interaction of prostate carcinoma and other cancers with bone but each site of molecular interaction may provide a therapeutic window for curtailing the effects of these tumors on the skeleton.
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PMID:Mechanisms of the development of osteoblastic metastases. 936 25


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