Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While studying Ag-pulsed syngeneic dendritic cell (DC) immunization, we discovered that surprisingly, unpulsed DCs induced protection against tumor lung metastases resulting from i.v. injection of a syngeneic BALB/c colon carcinoma CT26 or a syngeneic C57BL/6 lung carcinoma LL/2. Splenocytes or immature splenic DCs did not protect. The protection was mediated by NK cells, in that it was abrogated by treatment with anti-asialo-GM1 but not anti-CD8, and was induced by CD1(-/-) DCs unable to stimulate NKT cells, but did not occur in beige mice lacking NK cells. Protection correlated with increased NK activity, and increased infiltration of NK but not CD8(+) cells in lungs of tumor-bearing mice. Protection depended on the presence of costimulatory molecules CD80, CD86, and CD40 on the DCs, but surprisingly did not require DCs that could make IL-12 or IL-15. Unexpectedly, protection sensitive to anti-asialo-GM1 and increased NK activity were still present 14 mo after DC injection. As NK cells lack memory, we found by depletion that CD4(+) not CD8(+) T cells were required for induction of the NK antitumor response. The role of DCs and CD4(+) T cells provides a novel mechanism for NK cell induction and innate immunity against cancer that may have potential in preventing clinical metastases.
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PMID:Dendritic cell-induced activation of adaptive and innate antitumor immunity. 1463 94

It is well established that after metastatic cancer cells escape the primary tumour and enter the circulation, their interactions with microvascular endothelium of a target organ constitute an essential rate-limiting step in haematogenous cancer metastasis. However, the physiological and biochemical processes supporting neoplastic cell arrest and retention in the microcirculation are still poorly understood. In this study, we present experimental evidence that microvascular endothelium of metastasis-prone tissues undergoes activation in response to desialylated cancer-associated carbohydrate structures such as Thomsen-Friedenreich (TF) antigen (Galbeta1-3GalNAc) expressed on circulating glycoproteins and neoplastic cells. The metastasis-associated endothelium activation, manifested by marked increase in endothelial cell surface galectin-3 expression, causes gradual decrease in cancer cell velocities (from 72 x 10(2)+/- 33 x 10(2) microm s-1 to 7.6 x 10(2)+/- 1.9 x 10(2) microm s-1, mean +/-s.d.) accompanied by a corresponding increase in the percentage of rolling cells (from 3.3%+/- 1.2% to 24.3%+/- 3.6%, mean +/-s.d.), and results in human breast and prostate carcinoma cell arrest and retention in the microvasculature. This process, which could be of high importance in haematogenous cancer metastasis, was inhibited efficiently by an anti-TF antigen function-blocking antibody. Carbohydrate-mediated endothelial activation could be a process of physiological significance as it probably occurs in the interactions between a variety of circulating constituents and the vessel wall.
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PMID:Evidence of porcine and human endothelium activation by cancer-associated carbohydrates expressed on glycoproteins and tumour cells. 1467 94

Mucins are high-molecular weight epithelial glycoproteins with a high content of clustered oligosaccharides O-glycosidically linked to tandem repeat peptides rich in threonine, serine, and proline. There are two structurally and functionally distinct classes of mucins: secreted gel-forming mucins (MUC2, MUC5AC, MUC5B, and MUC6) and transmembrane mucins (MUC1, MUC3A, MUC3B, MUC4, MUC12, MUC17), although the products of some MUC genes do not fit well into either class (MUC7, MUC8, MUC9, MUC13, MUC15, MUC16). MUC1 mucin, as detected immunologically, is increased in expression in colon cancers, which correlates with a worse prognosis. Expression of MUC2 secreted gel-forming mucin is generally decreased in colorectal adenocarcinoma, but preserved in mucinous carcinomas, a distinct subtype of colon cancer associated with microsatellite instability. Another secreted gel-forming mucin, MUC5AC, a product of normal gastric mucosa, is absent from normal colon, but frequently present in colorectal adenomas and colon cancers. The O-glycosidically linked oligosaccharides of mucins can be described in terms of core type, backbone type, and peripheral structures. Colon cancer mucins have differences in both core carbohydrates and in peripheral carbohydrate structures that are being investigated as diagnostic and prognostic markers, and also as targets for cancer vaccines. Colon cancer mucins typically have increases in three core structures: Tn antigen (GalNAcalphaThr/Ser), TF antigen (Galbeta3GalNAc) and sialyl Tn (NeuAcalpha6GalNAc). The type 3 core (GlcNAcbeta3Ga1NAc) predominant in normal colonic mucin is lacking in colon cancer mucins. There are cancer-associated alterations in the peripheral carbohydrates of colonic mucins including a decrease in O-acetyl-sialic acid and a decrease in sulfation. There are, however, cancer-associated increases in sialyl LeX and related structures on mucins and other glycoproteins that can serve as ligands for selectins, increasing the metastatic capacity of colon cancer cells. The endogenous galactoside-binding protein galectin-3, which is expressed at higher levels in colon cancers than normal colon, binds to colon cancer mucin as well as other glycoproteins. Interference of the binding of selectins and galectin-3 to mucin may show therapeutic or preventative promise for colon cancer.
Cancer Metastasis Rev
PMID:Mucins and mucin binding proteins in colorectal cancer. 1500 Jan 51

Apparently synchronous, aggressive, mixed mesenchymal tumors in the right tibia, right femur, left femur, and rib cage produced multiple microscopic metastases in the lungs and macroscopic metastases in the liver, kidney, and spleen in a 1.5-year-old, neutered male, mixed-breed dog. No primary soft tissue tumor mass was present. Microscopically, the neoplasm exhibited osteosarcomatous, chondrosarcomatous, liposarcomatous, leiomyosarcomatous, fibrosarcomatous, angiosarcomatous, and leukocytic differentiation and was diagnosed as a multipotential osteosarcoma with various mesenchymal differentiation. Immunohistochemically, the neoplasm was cytoplasmically immunoreactive for vimentin, osteonectin, osteocalcin, CD 18, CD 31, desmin, and muscle-specific actin. Oil Red O staining was positive within liposarcomatous areas. Skeletal metastases from a primary bone tumor are exceedingly rare in human and veterinary medicine. However, the history, clinical signs, location, microscopic and immunohistochemical features were similar to those described in aggressive, poorly differentiated osteosarcomas of children. In addition, the wide range of mesenchymal tissue differentiation of this neoplasm was unusual, and to the authors' knowledge, an osteosarcoma with this degree of multiple differentiation has not been previously reported in the dog.
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PMID:Multipotential osteosarcoma with various mesenchymal differentiations in a young dog. 1513 75

The formation of hepatic metastases in colorectal cancer is the main cause of patient death. Current therapies directed at hepatic metastasis of colorectal cancer have had minimal impact on outcome. Therefore, alternative treatment strategies for liver metastasis require development. The present study was performed to evaluate the application of cDNA of LK68 encoding apolipoprotein(a) kringles IV-9, IV-10, and V as possible candidates for gene therapy treatment of this life-threatening disease. The murine colorectal cancer cell line CT26 was transduced ex vivo with LK68 cDNA via retroviral gene transfer, and an experimental model of hepatic metastasis was established by injecting LK68-expressing and control cells into the spleens of BALB/c mice. Expression of LK68 did not affect the growth characteristics and viability of transduced CT26 cells in vitro. LK68 produced from CT26 cells substantially inhibited the migration of endothelial cells in vitro. In vivo, substantial suppression of liver metastasis and prolonged survival were observed in mice bearing LK68-expressing CT26 cells, compared with controls. LK68-expressing liver metastases were restricted to smaller sizes and displayed decreased microvessel density and increased tumor cell apoptosis. Our data collectively indicate that LK68 suppresses angiogenesis-dependent progression of prevascular micrometastases to macroscopic tumors and their growth, which are clinically accessible and biologically relevant therapeutic targets. We propose that antiangiogenic gene therapy with LK68 is a promising strategy for the treatment of colorectal cancer liver metastasis.
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PMID:Suppression of colorectal cancer liver metastasis and extension of survival by expression of apolipoprotein(a) kringles. 1546 5

Women from families with multiple cases of breast and ovarian cancer, specifically those who carry cancer-associated mutations of BRCA1 or BRCA2 are at increased life-time risk for peritoneal carcinoma, even after previous surgery to remove the ovaries, fallopian tubes and uterus. Hereditary breast-ovarian cancer (HBOC) syndrome and the associated BRCA1 and BRCA2 mutations are particularly prevalent in women of Jewish lineage, and specific BRCA1 and BRCA2 germline mutations have been linked with peritoneal carcinoma and HBOC syndrome in Jewish populations, especially those of Ashkenazi descent. This review presents the currently available data and looks forward toward further and better understanding of peritoneal carcinoma in women with inherited susceptibility. Over 90% of peritoneal cancer in patients from HBOC syndrome kindreds and associated with BRCA1 and BRCA2 mutations are serous carcinomas, which is equivalent with the proportion of ovarian cancers that are serous carcinomas in similar patients. The best indications are that while many peritoneal carcinomas in genetically susceptible women may arise directly from malignant transformation of the peritoneum, others might represent metastases from primary ovarian or fallopian tube carcinomas. Although the incidence of borderline ovarian tumors may not be increased in HBOC syndrome kindreds and those who carry cancer-associated BRCA1 and BRCA2 mutations, these individuals could be susceptible to malignant transformation of borderline lesions of the ovaries and peritoneum. Moreover, recent reports raise the question of possibly increased risk in Jewish carriers of germline BRCA1 mutations for uterine papillary serous carcinoma, which could be the source of metastasis to the peritoneum in some cases. The penetrance of cancer-associated BRCA1 mutations for ovarian cancer is estimated to be 11%-54%, and for BRCA2 mutations the penetrance for ovarian cancer is 11%-23%. So far, available screening methods appear to be insufficient for early detection of many ovarian cancers. Prophylactic oophorectomy has been found to reduce the risk for ovarian cancer in women from HBOC kindreds and those who carry cancer-associated BRCA1 and BRCA2 mutations, leaving a residual risk for peritoneal carcinomatosis of well less than 5%. Therefore, surgical removal of the ovaries, fallopian tubes and uterus, after child-bearing has been completed and by early in the fifth decade of life, are appropriate prophylactic procedures in women whose genetic susceptibility puts them at increased risk for cancers of mullerian tract origin, including ovarian and fallopian tube carcinomas and possibly serous carcinoma of the uterus. Hysterectomy, as well as salpingo-oophorectomy, removes the gynecologic organs targeted for malignant transformation in genetically susceptible women and simplifies decisions regarding hormone replacement therapy and chemical prophylaxis and treatment of breast cancer. Unless a transabdominal operative approach is otherwise indicated, laparoscopic-assisted transvaginal techniques are well suited for intra-abdominal exploration, cytology, biopsies and prophylactic salpingo-oophorectomy and hysterectomy in women with hereditary susceptibility to gynecologic cancer.
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PMID:Peritoneal carcinoma in women with genetic susceptibility: implications for Jewish populations. 1551 51

We have previously observed a novel role of natural killer T (NKT) cells in negative regulation of antitumor immune responses against an immunogenic regressor tumor expressing a transfected viral antigen. Here, we investigated whether hidden spontaneous antitumor immunosurveillance, in the absence of a vaccine, could be revealed by disruption of this negative regulatory pathway involving CD4+ NKT cells and interleukin-13 (IL-13), in a murine pulmonary metastasis model of a nontransfected, nonregressor, syngeneic tumor, the CT26 colon carcinoma. Lung metastases of CT26 were decreased in CD4+ T cell-depleted BALB/c mice, suggesting that CD4+ T cells were involved in negative regulation of antitumor responses. CD1-knock out (CD1-KO) mice, which have conventional CD4+ T cells and CD4+CD25+ regulatory T cells but lack CD1-restricted CD4+ NKT cells, were significantly resistant to lung metastasis of CT26. The metastases were not further decreased in CD4+ T cell-depleted CD1-KO mice, implying that CD4+ NKT cells might be the primary negative regulator of antitumor immune responses in BALB/c mice. CD8+ T cells were found to act as effectors in antitumor immune responses, since the inhibition of lung metastases observed in naive CD1-KO or CD4+ T cell-depleted mice was abrogated by depletion of CD8+ T cells. Lung metastases were significantly decreased by treatment of mice with an IL-13 inhibitor, but not by deficiency or inhibition of IL-4. Thus, even for a nonregressor tumor, immunosurveillance exists but is negatively regulated via CD4+ NKT cells possibly mediated by IL-13, and can be unmasked by removal of these negative regulatory components.
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PMID:Unmasking immunosurveillance against a syngeneic colon cancer by elimination of CD4+ NKT regulatory cells and IL-13. 1552 92

Experimental hepatic metastasis of colorectal tumors is frequently studied by local intrahepatic tumor cell implantation. However, although a variety of factors of the implantation procedure may markedly influence tumor growth characteristics, standards are not defined yet. Herein, we studied the effect of different modes of cell implantation on tumor growth and angiogenesis by in vivo fluorescence microscopy and histology seven days after grafting colorectal CT26.WT tumor cells into the left liver lobe of syngeneic BALB/c mice. We demonstrate that (i) radial growth of cells implanted within the central area of the lobe is inhibited by a regularly observed fissura which crosses at midline the surface of the lobe; (ii) cells suspended during implantation in RPMI show an uncontrolled overwhelming growth 40-fold of those suspended in PBS; (iii) cell implantation in 100 microl and 20 microl suspension medium is significantly more complicated by rupture of the liver capsule, uncontrolled intraparenchymal cell spread and recoil of the cells through the injection canal compared to cells suspended in 10 microl; (iv) the frequency of metastasis within the injection canal and at the puncture site is significantly reduced using 32G compared to 27G or 29G needles; (v) occlusion of the puncture site by acrylic glue or electric coagulation completely abolishes peritoneal tumor spread compared to no treatment or gentle compression by cotton gauze. We conclude that a standardized growth of isolated metastases is best achieved by implanting CT26.WT cells in a 10 microl PBS blister subcapsularly into the paramedian area of the lower surface of the left liver lobe, using a 32-gauge needle and closing the puncture site with acrylic glue.
Clin Exp Metastasis 2004
PMID:Experimental liver metastasis: standards for local cell implantation to study isolated tumor growth in mice. 1567 70

Tumor metastasis is a major cause of mortality in cancer patients. The anti-metastatic effect of tetrandrine, an alkaloid isolated from Stephania tetrandrae S. Moore, was investigated in a pulmonary metastatic model of colorectal cancer-bearing mice. Tetrandrine decreased the viability of murine colorectal adenocarcinoma CT26 cells in a time- and dose-dependent manner. CT26 cells were injected into BALB/c mice via a tail vein to establish pulmonary metastases. After this, the mice were given intraperitoneal injections of tetrandrine (10 mg/kg/day), 5-fluorouracil (5-FU) at the same dose, or vehicle for 5 consecutive days. Mice treated with tetrandrine had 40.3% fewer metastases than vehicle-treated mice, and those treated with 5-FU had 36.9% fewer metastases than controls. Both tetrandrine- and 5-FU-treated mice survived longer than mice in the untreated control group. There was no acute toxicity or obvious changes in body weight in any of the mice. These results suggest that tetrandrine may be a useful anti-metastatic agent.
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PMID:Inhibitory effect of tetrandrine on pulmonary metastases in CT26 colorectal adenocarcinoma-bearing BALB/c mice. 1567 92

We have recently shown that the cancer-associated Sm-like protein (CaSm) is overexpressed in human pancreatic adenocarcinoma (PC). However, the role of CaSm in the process of neoplastic transformation remains unclear. To define further the role of CaSm in PC transformation, we have established a murine model based on the murine pancreatic cancer cell lines Panc02 and Panc03. CaSm is overexpressed in the aggressive Panc02 cells and expressed at much lower levels in the more indolent Panc03 cells. Up-regulation of CaSm in Panc03 cells increased in vitro proliferation and anchorage-independent growth and promoted subcutaneous tumor establishment and growth in syngeneic mice. Conversely, adenoviral down-regulation of CaSm in Panc02 led to significant inhibition of cellular proliferation and anchorage-independent growth in vitro and complete abolition of tumor growth and metastasis in vivo. Up-regulation of CaSm in NIH3T3 resulted in loss of contact inhibition and increased soft agar colony formation in vitro. The requirement for CaSm overexpression for neoplastic transformation confirms the concept that CaSm is a critical oncogene and potential target for molecular intervention. Furthermore, establishment of the murine clinically relevant model of pancreatic metastases provides a framework for the generation of preclinical data to support the development of novel molecular therapies targeting CaSm.
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PMID:Establishing a murine pancreatic cancer CaSm model: up-regulation of CaSm is required for the transformed phenotype of murine pancreatic adenocarcinoma. 1572 32


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