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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review concentrates on growth autonomy of tumor cells in relation to tumor progression. Human malignant melanoma serves as an example for progressive growth factor independence at subsequent stages of tumor progression. Mechanisms by which malignant cells acquire growth factor independence are discussed. In melanoma, deregulation of growth regulatory pathways has been described on four levels: 1) aberrant production of autocrine growth factors that substitute for exogenous growth factors (basic fibroblast growth factor [bFGF]); 2) alterations in the response to negative autocrine growth factors (interleukin [IL]-6 and transforming growth factor [TGF]-beta); 3) overexpression of epidermal growth factor receptors (EGF-R); and 4) alterations of cellular protooncogenes involved in signal transduction (RAS, MYB) and growth suppression (p53). In addition to bFGF and IL-6, multiple other growth factor genes are activated in malignant melanoma cells but not normal melanocytes. These include both chains of platelet-derived growth factor (PDGF), TGF-alpha, IL-1, IL-8, and tumor necrosis factor (TNF)-alpha. Of these, PDGF-B has been investigated in more detail. Melanoma-derived PDGF clearly does not act in a direct autocrine mode, but has important paracrine effects on normal tissue constituents, notably fibroblasts and endothelial cells, that are essential for tumor development in vivo. It is speculated that other melanoma-derived growth factors with as yet undefined functions similarly exert such paracrine or 'indirect' autocrine effects that cannot be sufficiently addressed in studies on cultured cells.
Cancer Metastasis Rev 1993 Sep
PMID:Growth factor independence and growth regulatory pathways in human melanoma development. 828 9

Type 1 transforming growth beta (TGF-beta 1) is a multifunctional regulator of cellular differentiation, motility and growth. It is capable of inhibiting or stimulating these processes depending on cell type, cell density, culture conditions and TGF-beta 1 concentration. TGF-beta 1 regulates growth, in part, by inducing the expression and secretion of various types of collagen, which participate in the control of cell adhesion and migration, as well as growth. TGF-beta 1 also regulates cell growth by controlling the response to epidermal growth factor (EGF) and other growth factors, in ways that can either decrease or increase their growth-promoting effects. Alterations in both negative and positive growth responses to TGF-beta 1 play important roles in tumor progression. Loss of sensitivity to growth inhibition by TGF-beta 1 can occur as a result of decreased expression of collagen. Acquisition of sensitivity to growth stimulation, and autocrine transformation by TGF-beta 1, are associated with aberrant EGF receptor regulation. Aberrant growth factor receptor regulation by TGF-beta 1 may be mediated by a protein kinase C (PKC)-dependent pathway which inhibits degradation of growth factor receptor/ligand complexes. The evidence reviewed is consistent with a minimal two-step mechanism for autocrine transformation, which involves production of growth factor and enhanced cellular response as a result of aberrant membrane traffic. Defects in membrane traffic regulation may provide an explanation for common alterations in tumor cell response to both multiple growth inhibitors and growth stimulators, and may also suggest novel approaches to cancer chemotherapy.
Cancer Metastasis Rev 1993 Sep
PMID:Transforming growth factor beta and the cell surface in tumor progression. 828 11

Prostate adenocarcinoma, the most common tumor occurring among North American men, preferentially metastasizes to bone, where it characteristically forms osteoblastic lesions. The following growth regulatory factors are expressed in some human prostate cancers and/or established cell lines: epidermal growth factor (EGF), transforming growth factor alpha, transforming growth factor beta, basic fibroblast growth factor (bFGF), and insulin-like growth factor. Some of these, especially EGF, bFGF, and TGF-beta, are also implicated in growth regulation in normal and benign hyperplastic prostates. Although evidence from in vitro study of the small number of prostate cell lines available demonstrates that these growth regulatory pathways are exploited by some of these cells, direct in vivo evidence is limited. The development of human prostate cancer cell lines which grow and metastasize in immune-deficient rodents is an advance which now permits experimental analysis of the role of these growth factors in prostatic metastasis, particularly to bone. The progression and metastasis of human prostate cancer results from the complex interactions of multiple growth factors, androgens, and cellular communication, which form a dynamic network. Continued progress in the study and treatment of this disease will require new conceptual frameworks as well as successful application of the techniques of molecular and cellular biology.
Cancer Metastasis Rev 1993 Sep
PMID:Growth factors and their receptors as determinants in the proliferation and metastasis of human prostate cancer. 828 14

Levels of epidermal growth factor (EGF) receptor expression were investigated in five basal cell epitheliomas (BCEs) and 10 primary lesions from squamous cell carcinoma (SCC) of the skin, using light microscopic autoradiography with [125I]EGF. All of the BCEs were clinically the pigmented type and histologically the solid type. All of them showed an EGF binding level similar to that of the basal and suprabasal layers of the normal epidermis. The SCCs included one case of Bowen's disease (SCC in situ), five of the well differentiated type, three of the moderately differentiated type and one of the poorly differentiated type. Eight of the 10 SCCs showed an EGF binding level similar to that of the normal epidermal basal and suprabasal cell layers. One of the two remaining SCCs, a moderately differentiated type, showed highly increased EGF binding. The other one, a poorly differentiated type, showed very little EGF binding in a large region consisting of poorly differentiated cells, although a small area composed of more differentiated, nest-forming cells had an EGF binding level similar to that of the basal and suprabasal cells. Metastasis was found in three of these 10 SCCs after surgery. Two of the three SCCs with metastasis showed increased or decreased EGF binding levels in primary lesions as described above; in contrast, primary lesions of the seven SCCs without metastasis had EGF binding levels similar to those of the normal epidermal basal and suprabasal cells. Abnormally increased or decreased EGF binding level in SCC of the skin may be indicative of a poor prognosis, although it is necessary to examine more SCCs to confirm this assumption.
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PMID:Light microscopic autoradiographical analysis of [125I]epidermal growth factor binding in basal cell epithelioma and squamous cell carcinoma of the skin. 831 11

Type II estrogen-binding sites (Type II EBS) and the recently identified bioflavonoid-like ligand methyl-p-hydroxyphenyllactate may be regarded as a growth regulatory system active on both normal and neoplastic tissues. It has been reported that, in addition to estrogen and progesterone receptors, primary ovarian cancers also express Type II estrogen binding sites. These sites are able to bind estrogenic compounds and also some naturally occurring flavonoids such as quercetin. In this study we report the presence of cytosolic Type II EBS in a series of 10 normal ovaries, 42 primary ovarian tumors, and 14 metastatic deposits. Scattered levels of Type II EBS were found in normal ovarian tissues (median, 1603 fM/mg protein, range, 271-4943). In primary ovarian tumors and in omental metastases median levels of Type II EBS were 835 fM/mg protein (range, 134-4875) and 758 fM/mg protein (range, 204-2007), respectively. Although Type II EBS tend to be higher in normal than in malignant tissues the difference was not statistically significant. No correlation was found between Type II EBS levels and the common clinicopathological characteristics of the tumors. Moreover there was no relation between Type II EBS and estrogen and epidermal growth factor receptors. A significative inverse correlation with progesterone receptor levels was observed. The presence of Type II EBS in ovarian cancer could be of clinical importance since it has been demonstrated that bioflavonoids, through the interaction with Type II EBS, may exert a growth inhibitory activity both alone or in combination with chemotherapeutic agents on ovarian cancer cell lines and primary tumors.
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PMID:Type II estrogen-binding sites in human ovarian cancer: correlation with estrogen, progesterone, and epidermal growth factor receptor. 848 62

Forty oral squamous cell carcinomas have been investigated immunohistochemically for the presence of transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF). The same cases were recently characterized for the expression of EGF-receptors. TGF-alpha was detected with a monoclonal mouse antibody and EGF with polyclonal rabbit antiserum. Thirty-five of the tumours were positive for TGF-alpha and 26 of the tumours for EGF. None of the poorly differentiated tumours was positive for EGF, but they all were for TGF-alpha. In sections including normal differentiated oral mucosa, the cells above the basal cell layer were positive for both TGF-alpha and EGF. The same staining pattern was observed in oral mucosa obtained from healthy persons. In moderately to well differentiated carcinomas, the immunoreactivity was mainly confined to the cytologically more differentiated cells, thus paralleling the situation observed in the normal differentiated oral mucosa. In four cases, material was available from both a primary tumour and a metastasis. Three of these were positive for TGF-alpha and EGF with the same staining pattern as that of the primary tumours. This investigation together with our previous results confirms the existence of TGF-alpha, EGF, and EGF-receptors in the majority of oral squamous cell carcinomas and their metastases.
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PMID:Immunoreactive transforming growth factor alpha and epidermal growth factor in oral squamous cell carcinomas. 849 25

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

The potent vasoconstrictor endothelin-1 (ET-1) is at its highest concentration in the normal human ejaculate and is associated with the progression of metastatic prostate cancer. ET-1 protein expression is detected in situ in 14 of 14 primary cancers and 14 of 16 metastatic sites of human prostatic carcinoma. Exogenous ET-1 induces prostate cancer proliferation directly and enhances the mitogenic effects of insulin-like growth factor I, insulin-like growth factor II, platelet-derived growth factor, basic fibroblast growth factor, and epidermal growth factor in serum-free conditions in vitro. The ETA-selective receptor antagonist A-127722 inhibits ET-1-stimulated growth, but the ETB-selective receptor antagonist BQ-788 does not. ET-3, an ETB-selective agonist, also had no effect on prostate cancer growth. No specific ETB-binding sites could be demonstrated in any established human prostate cancer cell line tested, and ETB mRNA, detected by reverse transcription PCR, was reduced. The predominance of ETB binding on human benign prostatic epithelial tissue is not present in metastatic prostate cancer by autoradiography. In human prostate cancer progression to metastases, ET-1 and ETA expression are retained, whereas ETB receptor expression is reduced.
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PMID:Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer. 863 Sep 91

Patients with recurrent or high-grade superficial transitional-cell carcinoma of the bladder that has recurred after intravesical chemotherapy are at increased risk for tumor invasion and metastases. Intravesical chemotherapy is a minimally invasive technique that allows high doses of therapeutic agents to be delivered directly to the malignancy, doses that would not be tolerated systemically. In vitro studies demonstrate suramin's significant efficacy against transitional-cell carcinoma cell lines at relatively low doses. Humans treated with similar doses delivered in a systemic fashion have experienced no bladder toxicity. Suramin has been shown to block the binding of epidermal growth factor (EGF) to its receptors, which are found in large amounts in bladder cancers. Because a significant association has been found between the number of EGF receptors on a bladder-cancer cell and its sensitivity to suramin, transitional-cell carcinoma could potentially be very responsive to such therapy. On the basis of these findings, a phase I escalating-suramin-dose study is currently being conducted.
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PMID:Intravesical suramin: a novel agent for the treatment of superficial transitional-cell carcinoma of the bladder. 873 3

We have developed a model of human squamous epithelial cell invasion in human skin organ culture. Epidermal invasion of the dermis occurs in this model when the tissue is exposed to an exogenous source of epithelial cell growth factor. In the present study we sought to determine to what extent growth factor-induced invasion correlates with the ability of the growth factor to induce epithelial cell motility. Histological examination of tissue treated with epidermal growth factor (EGF), hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1) or keratinocyte growth factor (KGF) showed that only HGF and EGF were inducers of invasion while KGF- and IGF-1-treated tissues were histologically similar to untreated controls. In parallel studies, HGF and EGF were found to be potent stimulators of epidermal keratinocyte motility while IGF-1 was less effective and KGF was even less so. None of the growth factors stimulated dermal fibroblast motility while HGF and to a lesser extent IGF-1 (but not EGF or KGF) stimulated motility of dermal vascular endothelial cells. Thus, there is a strong correlation between growth factor capacity to induce epidermal keratinocytes to invade the underlying dermal tissue and to induce motility in the invasive population of cells.
Invasion Metastasis 1996
PMID:Growth factor-induced epidermal invasion of the dermis in human skin organ culture: dermal invasion correlated with epithelial cell motility. 883 Jul 60


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