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 on a patient with a follicular Hurthle cell carcinoma in whom distant metastases were initially radioiodine negative or only weakly positive. Redifferentiation therapy with 13-cis retinoic acid induced a significant radioiodine uptake in metastatic tissue. Thyroglobulin (Tg) immunostaining and autoradiography of a bone metastasis in the right femur, which was initially radioiodine negative, proved Tg synthesis, combined with iodine incorporation into tumor cells. Glucose metabolism in metastases was partially increased and partially unchanged after redifferentiation therapy. The distinct increase of serum Tg after retinoic acid treatment was interpreted as a functional sign of redifferentiation.
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PMID:Redifferentiation therapy with retinoic acid in follicular thyroid cancer. 974 42

Both normal and malignant prostatic epithelial cells in culture secrete urokinase-type plasminogen activator (u-PA) into the culture medium. u-PA has been shown to have a direct association with invasive and metastatic potential of many types of cancers. We propose that prostate cancer has the intrinsic ability to invade and metastasize because of its inherent ability to secrete the serine protease u-PA. We further propose that in prostate cancer, u-PA is the key enzyme which occupies a place at the apex of the proteolytic cascade and initiates the degradative process. Subsequently, collagenases are recruited after activation of procolla-genases by another serine protease plasmin formed by the activation of plasminogen by u-PA. Extracellular proteolysis involving plasmin can cause massive degradation of the extracellular matrix. We show that u-PA alone can use fibronectin as a substrate and degrade it, but u-PA alone did not degrade laminin. Serum-free conditioned medium from DU-145 human prostatic carcinoma cells has the ability to degrade both fibronectin and laminin. However, treatment of cultures with 1 microM all-trans retinoic acid (RA) for 48 h reduced the ability of serum-free conditioned medium to cause u-PA-mediated degradation of fibronectin and laminin. Thus, RA had a protective effect on these extracellular matrix glycoproteins. Treatment of cells with RA also decreased their ability to invade Matrigel in the in vitro invasion assay in a dose-dependent manner. RA at the 0.5, 1, and 10 microM level reduced invasion to 65.7%, 46.7%, and 34.3% of control, respectively. RA reduced extracellular proteolysis and thus inhibited extracellular matrix degradation and invasion. These results may also explain one mechanism by which retinoids inhibit invasion and metastasis in vitro and in vivo. These studies have important translational value in the chemoprevention of progression of prostatic intraepithelial neoplasia to invasive carcinoma.
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PMID:Urokinase-mediated extracellular matrix degradation by human prostatic carcinoma cells and its inhibition by retinoic acid. 981 42

Differentiated thyroid cancer accounts for a majority of the nearly 200,000 people in the United States with thyroid cancer. A significant minority of patients with thyroid cancer do not respond to conventional therapy (surgery, radioiodine, levothyroxine [LT4]). Current therapy for progressive, radioiodine non-responsive differentiated thyroid cancer includes surgery and external-beam irradiation (with or without low-dose weekly Adriamycin) for neck disease, and high-dose Adriamycin therapy for widely metastatic disease. Adriamycin therapy provides a 30% to 40% partial response of disease, but long-term cures are rare. Studies of combination chemotherapy do not show greater benefit than therapy with Adriamycin alone and carry understandably greater toxicity. Retinoic acid, octreotide, and tamoxifen therapies are currently being studied as future therapeutic possibilities. Chemotherapy may prove useful not only as a tumoricidal agent but as therapy for tumor re-differentiation in preparation for radioiodine therapy.
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PMID:Management of the patient with progressive radioiodine non-responsive disease. 989 Jul 38

Neural cell adhesion molecule (NCAM) is down-regulated during periods of embryological cell migration and may be important in local tumor migration or metastases. Conflicting information exists in the literature about NCAM expression in human glial tumors and little is known about its expression in human brain metastases. We immunohistochemically stained a panel of 43 primary human brain tumors and their cultured counterparts for NCAM including glioblastoma multiformes, anaplastic astrocytomas, oligodendrogliomas, and contrasted their staining with a panel of 3 meningiomas, 11 brain metastases, and 5 normal brain samples utilizing the monoclonal antibody NKH-1. Most gliomas and metastatic melanomas and lung carcinomas showed a high percentage of cells positive for NCAM expression while NCAM staining was negative for other carcinomas. No difference was seen between intensity or percentage of cells that were NCAM positive, based on tumor grade or type. In glioma cell lines, NCAM expression was lost upon passage. In 15 glioma cell lines we also determined NCAM isoform expression by reverse transcription/polymerase chain reaction (RT/PCR) and found that 6 of 15 had message for NCAM 180, 8 of 15 for NCAM 140, and only 3 of 15 had message for NCAM 120. Normal brains always contained message for the 180 isoform and usually had mRNA for all 3 isoforms. Using monoclonal antibodies for retinoic acid receptor alpha (RAR alpha), we found nuclear staining in melanomas and lung carcinomas metastatic to brain and only rarely in gliomas. Neither the relative antigen density of NCAM nor the percent of NCAM-positive cells appreciably changed upon incubation with retinoic acid (RA), as measured by flow cytometry. RAR alpha was not found at a level measurable by immunohistochemistry in nuclei of most glial tumors, providing an explanation for why RA might not induce NCAM expression. Whether paucity of RAR alpha on primary gliomas might also correlate with results from clinical trials showing limited efficacy of RA in treatment of human gliomas awaits further study.
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PMID:Paucity of retinoic acid receptor alpha (RAR alpha) nuclear immunostaining in gliomas and inability of retinoic acid to influence neural cell adhesion molecule (NCAM) expression. 1022 20

As clinical oncologists, our ultimate goal in treating patients with cancer is to be able to cure their disease with a combination of treatment modalities directed at the primary tumor (surgery or radiation), and potential metastases (chemotherapy). The validity of this multimodality approach to treating cancer was initially demonstrated with the successful treatment and cure of highly chemosensitive childhood cancers, such as Wilms' tumor, and these cures were only realized when adjuvant chemotherapy was included with local control measures. We attribute our treatment successes in childhood cancers to the use of cytotoxic chemotherapy, and we attribute our inability to cure many adults with more common forms of solid tumors to the ineffectiveness of chemotherapy in these diseases. Curing disease is not the goal of most pharmacological interventions in nonmalignant diseases. With the exception of antimicrobial and anticancer chemotherapy, most of the common classes of drugs are administered with the intent of controlling the disease or the symptoms caused by disease. We administer antihypertensive agents to control blood pressure, but the underlying cause of the hypertension is not cured by this therapy. If the hypertension recurs after antihypertensive therapy is stopped, we would conclude that the therapy was successful at controlling the disease. However, if a patient's tumor relapses after completing anticancer chemotherapy, the anticancer therapy would be considered to be unsuccessful. By setting lofty goals for our therapy, we increase the probability that the treatment will not meet our own and our patient's expectations. Schipper et al. [J Clin Oncol 1995;13:801-805] proposed that we abandon the "killing paradigm," which dictates that the treatment of cancer is directed toward eradication of all cancer cells, and that we adopt a "regulatory model" of cancer. This model views cancer as a maladaptive, constantly evolving process in which cancer cells differ only slightly from normal cells as a result of a few critical genetic changes that lead to dysregulation of growth. The treatment approach under this new paradigm is debulking of tumor burden with standard multimodality therapy followed by control of residual disease by "reregulation" of the remaining cancer cells. Controlling growth and spread of this residual disease would be accomplished with non-cytotoxic agents which target pathways that are responsible for the dysregulation in cancer cells. We are now on the verge of having the capacity to test this new paradigm of cancer. Advances in our understanding of the pathogenesis of many common forms of cancer at a molecular level have led to a revolution in anticancer drug development. A number of new agents that target a variety of critical molecular targets, such as the farnesyl transferase inhibitors that block ras oncogene activation, the matrix metalloproteinase inhibitors that block the enzymes involved in tissue invasion and metastasis [Editor's note: please see "New Drugs on the Horizon, page 271], and the angiogenesis inhibitors that block new vessel formation in growing tumors, are now being clinically tested. These new classes of anticancer drugs are aimed at regulating or controlling cancers rather than killing them. The potential utility of targeting the critical molecular lesion in tumor cells is illustrated by the efficacy of all-trans-retinoic acid in acute promyelocytic leukemia (APL). Although the capacity of all-trans-retinoic acid to induce complete remissions by inducing terminal differentiation of leukemic blasts was discovered empirically, the subsequent demonstration that the pathognomonic 15:17 translocation that is present in up to 90% of cases of APL results in the production of a dysfunctional retinoid receptor appears to explain the specificity and high level of activity of retinoid therapy in this disease. This is the first example of a cancer that can be treated by specifically targeting therapy to a pathogenetic molecular lesion. Retinoids are now being used in combination with standard chemotherapy for the treatment of APL, an example of the successful application of combining a molecularly targeted agent with conventional cytotoxic chemotherapy. The development and use of molecularly targeted agents for the treatment of cancer may require us to view cancer in a new light and to adjust our goals and expectations of its treatment as well as the endpoints of our clinical trials. However, pharmacologically controlling cancer may result in an equally acceptable outcome for our patients if it leads to what Schipper et al. termed a "functional cure."
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PMID:The Goal of Cancer Treatment. 1038 18

Matrix metalloproteinases (MMPs) play an important role in tumor cell invasion and metastasis. These processes require the dissolution of the basement membrane and invasion of the stromal matrix (ECM), and are mediated by MMPs. Consequently, MMP inhibitors may be attractive as new anticancer agents. To examine the potential contribution of collagenase-1 (MMP-1) in invasion of stromal matrix, we used the highly invasive and metastatic breast cancer cell line MDA-MB-231 as a model system. These cells express procollagenase-1 constitutively and this expression can be repressed by all-trans retinoic acid. Invasion of these cells into a collagen type I matrix was assessed by scanning electron microscopy (SEM), and was quantitated with a computer program and confocal laser scanning microscopy (CLSM). We found that MDA-MB-231 cells freely invaded the collagen type I matrix, suggesting that these cells possess a mechanism for activating the latent collagenase-1. In contrast, down-regulation of collagenase-1 expression by all-trans retinoic acid caused these cells to become less invasive. To confirm a role for collagenase-1 in mediating collagen type I invasion, assays were carried out in the presence of FN-439, an inhibitor of collagenase-1 enzyme activity. We found that in the presence of the proteinase inhibitor, invasion of type I collagen by MDA-MB-231 cells was also reduced. These results indicate that collagenase-1 produced by the breast tumor cells may enhance stromal matrix degradation by enabling the tumor cells to modulate their own invasive behavior, and suggest that decreasing collagenase-1 levels may be effective in breast cancer therapy.
Clin Exp Metastasis 1999 May
PMID:Human breast cancer cells activate procollagenase-1 and invade type I collagen: invasion is inhibited by all-trans retinoic acid. 1043 8

A long latent period of 20 to 30 years may be involved in the multistep process of carcinogenesis represented by prostatic intraepithelial neoplasia (PIN) in the prostate. It is, therefore, possible that progression to a malignant state could be blocked or reversed during this time. Retinoids not only have the ability to block steps in the process of carcinogenesis but they may also modulate or reverse some malignant characteristics of cancer cells. This study focuses on the ability of N-(4-hydroxyphenyl)-retinamide (4-HPR), a synthetic retinoid, to reverse malignant characteristics towards a normal phenotype, using the human prostate carcinoma cell line DU-145. These malignant characteristics include abnormal cell proliferation, intermediate filament expression, motility, invasion, and cell survival. Results show that 1 microM and 10 microM 4-HPR caused 31% and 96% inhibition of growth, while all-trains retinoic acid (ATRA) produced similar effects at 10 and 100 microM, making 4-HPR ten times more effective than ATRA. While DU-145 cells show strong immunostaining for vimentin, treatment with 1 microM 4-HPR for eight days caused a marked decrease in vimentin staining. This was accompanied by a change from an elongated to an epithelial cell morphology. Densitometric analysis of Western blots for vimentin showed a 53% decrease in vimentin expression in 1 microM 4-HPR treated cells. Concomitant with the decrease in vimentin expression, cell motility and invasive ability also decreased by 32% and 52%, respectively. Growth inhibition was accompanied by DNA fragmentation and apoptosis. Exposure of cells to 1 microM 4-HPR caused a marked upregulation of nuclear retinoid receptors RARalpha and a detectable expression of RARgamma. These results suggest that inhibition of growth and vimentin expression, and induction of apoptosis by 4-HPR in prostate cancer cells may occur via a receptor-mediated mechanism involving transrepression of AP-1 by retinoid receptors. We propose that vimentin may serve as a useful intermediate marker for early detection of prostate cancer in biopsy specimens and that 4-HPR may be effective in blocking several steps in prostate carcinogenesis as well as the progression of PIN to invasive carcinoma.
Clin Exp Metastasis 1999 May
PMID:Modulation of the malignant phenotype of human prostate cancer cells by N-(4-hydroxyphenyl)retinamide (4-HPR). 1043 11

We present a case of increased I-131 uptake in a patient with papillary thyroid carcinoma with local recurrence and distant metastases after a second treatment with retinoic acid as a sign of redifferentiation of the tumor cells. When fine-needle aspiration cytology before and after a second course of retinoic acid treatment were compared, signs of tumor cell redifferentiation were found. This was accompanied by biochemical reexpression of thyroid marker proteins.
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PMID:Increased I-131 uptake in local recurrence and distant metastases after second treatment with retinoic acid. 1055 65

Cancer cell attachment to and invasion of the extracellular matrix has been associated with the metastatic potential of cell lines of the Dunning R-3327 rat prostatic adenocarcinoma model. We investigated the cell-matrix interactions of prostate tumor cells by comparing the invasive ability through reconstructed extracellular matrix and attachment upon EHS NATRIX (natural extracellular matrix), fibronectin, laminin, and collagen Type IV. We observed a correlation between metastatic potential and substrate dependence of attachment in prostate cancer cells. Nonmetastatic AT-1 cells possessed a higher adhesive potential to extracellular matrix components than the highly metastatic cells (ML, MLL and AT-3). It was also found that the invasive potential of the three highly metastatic cell lines was significantly higher than that of the nonmetastatic cell line. Here, it is reported that the ability to traverse a matrigel matrix correlates with their metastatic potential. These observations suggest that the extracellular matrix components are highly involved in influencing prostate cancer cell activities. In addition, we investigated the effects of two differentiation agents, retinoic acid (RA) and difluoromethylornithine (DFMO), on the adhesive and invasive profiles of the tumor cells. After treatment with both agents, adhesion was increased to levels not different from nonmetastatic cells. Furthermore, the ability of highly metastatic cells to traverse a matrigel barrier was significantly reduced after treatment with both differentiation agents. These results suggest that RA and DFMO are capable in reversing the metastatic potential of prostate cancer cells in vitro and may give a possible insight into their role as potential therapeutic agents in vivo.
Invasion Metastasis
PMID:Invasive potential and substrate dependence of attachment in the dunning R-3327 rat prostate adenocarcinoma model. 1064 Sep 2

Pulmonary metastasis is a major cause of death and a major obstacle to the successful treatment of canine osteosarcoma. However, the residual capacity of the neoplasia for differentiation and its susceptibility to undergo apoptosis may be used to suppress its growth and metastatic properties. The highly metastasizing POS (HMPOS) canine osteosarcoma cell line which preferentially metastasize to the lungs was used to test the possible efficacy of 22-oxa-calcitriol (OCT) and all- trans retinoic acid (ATRA) to inhibit growth and pulmonary metastasis of the subcutaneously grown osteosarcoma in nude mice. Treatments in vitro, morphologically elongated and increased alkaline phosphatase activity and staining of cells. Tumour growth in vivo was inhibited significantly and the combination treatment of OCT and ATRA (OCT + ATRA) exerted a synergistic and stronger suppression at concentration of 1.0 microg kg(-1)body weight when given subcutaneously three times a week for 5 weeks. The subcutaneous tumours of the control mice consisted of osteoblast-like cells and isolated chondroblast-like cells, but formed several areas of osteoid and increased amount of collagen tissue in all treated mice. Pinpoint macrometastatic nodules developed only in all control mice. Micrometastatic nodule developed only in two of six mice treated with ATRA. However, nodule size and number, and lung wet weight were all reduced significantly. Metastasis were not seen in the mice treated with OCT or OCT + ATRA. This study demonstrated that inhibition of growth and pulmonary metastasis was induced by subcutaneous treatment with these drugs and suggest that both its differentiating and apoptotic inducing activities may be responsible for the antitumour effects. These drugs may be useful in the clinic as an adjunct for the treatment of canine osteosarcoma.
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PMID:Inhibitory effects of 22-oxa-calcitriol and all- trans retinoic acid on the growth of a canine osteosarcoma derived cell-line in vivo and its pulmonary metastasis in vivo. 1068 63


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