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PubMed2002

Radiosurgery for residual or recurrent nonfunctioning pituitary adenoma.

OBJECT: Nonfunctioning pituitary adenomas comprise approximately 30% of all pituitary tumors. The purpose of this retrospective study is to evaluate the efficacy and role of gamma knife radiosurgery (GKS) in the management of residual or recurrent nonfunctioning pituitary adenomas. METHODS: A review was conducted of the data obtained in 42 patients who underwent adjuvant GKS at the University of Pittsburgh between 1987 and 2001. Prior treatments included transsphenoidal resection, craniotomy and resection, or conventional radiotherapy. Endocrinological, ophthalmological, and radiological responses were evaluated. The duration of follow-up review varied from 6 to 102 months (mean 31.2 months). Fifteen patients were observed for more than 40 months. The mean radiation dose to the tumor margin was 16 Gy. Conformal radiosurgery planning was used to restrict the dose to the optic nerve and chiasm. Tumor control after GKS was achieved in 100% of patients with microadenomas and 97% of patients with macroadenomas. Gamma knife radiosurgery was equally effective in controlling adenomas with cavernous sinus invasion and suprasellar extension. No patient developed a new endocrinological deficiency following GKS. One patient's tumor enlarged with an associated decline in visual function. Another patient experienced a deterioration of visual fields despite a decrease in tumor size. CONCLUSIONS: Gamma knife radiosurgery can achieve tumor control in virtually all residual or recurrent nonfunctioning pituitary adenomas. Dose sparing facilitates tumor management even when the adenoma is close to the optic apparatus or invades the cavernous sinus.

Adenoma↗

PubMed2001

Metastatic human hepatocellular carcinoma models in nude mice and cell line with metastatic potential.

Metastatic human HCC model is needed for the studies on mechanism and intervention of metastatic recurrence. By using orthotopic implantation of histologically intact tissues of 30 surgical specimens, a patient-like metastatic model of human HCC in nude mice (LCI-D20) and a low metastatic model of human HCC in nude mice (LCI-D35) have been established. All mice with transplanted LCI-D20 tumors exhibited extremely high metastatic ability including spontaneous metastasis to liver, lungs, lymph nodes and peritoneal seeding. Remarkable difference was also found in expression of some of the invasiveness related genes and growth factors between the LCI-D20 and LCI-D35 tumors. PAI-1 increased gradually following tumor progression in LCI-D20 model, and correlated with tumor size and AFP level. Phasic expression of tissue intercellular adhesion molecule-1 in this model was also observed. Using corneal micropocket model, it was demonstrated that the vascular response induced by LCI-D20 tumor was stronger than that induced by LCI-D35 tumor. Similar report on metastatic human HCC model in nude mice and human HCC cell line with metastatic potential was rarely found in the literature. This LCI-D20 model has been widely used for the studies on intervention of metastasis, including anti-angiogenesis,antisense approach, metalloproteinase inhibitor, differentiation inducer, etc. It is concluded that the establishment of metastatic human HCC model in nude mice and human HCC cell line with metastatic potential will provide important models for the in vitro and in vitro study of HCC invasiveness, angiogenesis as well as intervention of HCC recurrence.

Animals↗

PubMed2006

Epigenetic transfer of metastatic activity by uptake of highly metastatic B16 melanoma cell-released exosomes.

AIM: To investigate potential role of highly metastatic BL6-10 tumor cell-released exosomes (EXO) in transfer of metastatic activity into poorly metastatic tumor cell line F1. METHODS: The highly metastatic B16 melanoma cell line (BL6-10) was generated in our laboratory. EXO from this cell line were isolated and amount of exosomal recovered proteins was measured using Bradford assay. For phenotypic analysis BL6-10 and F1 melanoma cells were stained with FITC-conjugated anti-MHC I (H-2K(b)), MHC II (Ia(b)) and Met 72 antibodies and analyzed by flow cytometry. C57BL/6 mice (8 per group) were injected (i. v.) with 0.5 x 10(6) F1, BL6-10 and F1(EXO) melanoma cells. Lungs were removed 4 weeks after tumor cell injection, fixed in 10% neutral buffered formaldehyde and embedded in paraffin for histological analysis. RESULTS: Data revealed that BL6-10 cells expressed metastasis marker (Met 72 tumor antigen), while F1 cells did not display this cell surface marker. All mice inoculated with BL6-10 melanoma cells had numerous lung tumor colonies, while mice injected with F1 tumor cells were free of lung metastatic colonies. BL6-10 tumor cells-released EXO also expressed Met 72 tumor antigen as BL6-10 tumor cells, but in less amount. F1 tumor cells can uptake EXO from BL6-10 tumor cells and express acquired exosomal Met 72 tumor antigen. CONCLUSION: The metastatic activity of highly metastatic BL6-10 tumor cells can be transferred to poorly metastatic F1 tumor cells by uptake of highly metastatic BL6-10 tumor-released EXO.

Animals↗

PubMed1983

Characterization of metastatic clones derived from a metastatic variant of mouse colon adenocarcinoma 26.

A spontaneously metastatic variant (P-26-select) was selected from the murine colon adenocarcinoma 26 after repeated (26 times) cyclic in vivo passage of tumor cells from the lungs of mice bearing s.c. tumors. Clones were established from the cultured P-26-select cell line. These clones, the parent [P-no-select (culture cell line of colon 26 without in vivo selection)] and the metastatic variant (P-26-select) were then studied using three different assays to determine their metastatic potential. These assays included experimental metastasis, spontaneous metastasis from a nonresected s.c. growing tumor, and spontaneous metastasis following the resection of a primary footpad tumor. In general, there was an agreement among the results of these three assays of metastases, i.e., if a variant was spontaneously metastatic, it was also metastatic in the other assays of metastases. However, some experimentally metastatic clones did not necessarily show a high spontaneous metastatic potential to the lung. These results might indicate that the metastatic variant (P-26-select) is populated by spontaneously metastatic clones and also by clones which possess a propensity to metastasize experimentally. The morphology and growth properties of the clones were compared also.

Adenocarcinoma↗

PubMed1991

Clonal selection within metastatic SP1 mouse mammary tumors is independent of metastatic potential.

Our previous studies using randomly integrated plasmid DNA as unique clonotypic markers of SPI mouse mammary tumor cells transplanted into syngeneic CBA/J or nude mice demonstrated reproducible selection and eventual overgrowth of the primary transplant tumors by genotypically distinct metastatic subclones. Two independent metastatic SPI clones, neo5 and ras1, were shown to exhibit "clonal dominance" relative to the non-metastatic SPI tumor-cell population. These results suggested that the capacity for preferential growth within the tumors may be related to cellular properties associated with metastatic ability. To investigate the clonal interactions of metastatic SPI clones present within the same tumor mass, we have analyzed tumors composed of paired mixtures of neo5 and ras1. The tumors were monitored for the relative proportion of each clone by Southern blot analysis. The ras1 clone was found to dominate over the neo5 clone in the majority of tumors examined, even when present as 1% of the mixed inoculum. This represents a 20- to 50-fold enrichment of ras1, while the proportion of neo5 within the tumors was reduced at least 5-fold. No evidence for selection of either clone was seen during co-culture in vitro. Neo5 and ras1 are indistinguishable with respect to tumorigenic and metastatic potential when inoculated separately into different mice, suggesting that clonal dominance is independent of metastatic ability. Analysis of the metastases resulting from mixed inocula indicates that it is possible for a subpopulation representing less than 1% of the primary tumor mass to give rise to metastases. This also suggests that the process of metastasis within metastatic tumors is independent of clonal dominance.

Adenocarcinoma↗

PubMed1995

Cloning and identification of genes differentially expressed in metastatic and non-metastatic rat rhabdomyosarcoma cell lines.

The objective of this study was to identify genes involved in invasion and metastasis using a rat rhabdomyosarcoma model (SMF-A and RMS-B cell lines). The SMF-A cell line was established from a metastatic nodule of an induced rhabdomyosarcoma in syngeneic F344 rats. Two cell lines with defined metastatic potentials, SMF-Ai and SMF-Da, were cloned from the SMF-A line. The cell line SMF-Ai is tumorigenic, highly invasive and highly metastatic. On the other hand, the revertant line SMF-Da is less tumorigenic, non-invasive and non-metastatic. We have isolated from a SMF-Ai cDNA library eight cDNA clones which are differentially expressed by the metastatic SMF-Ai and the non-metastatic SMF-Da cell line using Northern blot analysis. Five of these clones, smf-4, smf-6, smf-41, smf-42 and smf-44, are overexpressed in the SMF-Da cell line and have homology with beta-2-microglobulin, lactate dehydrogenase, ribosomal protein L38, ribosomal protein S4 and acidic ribosomal phosphoprotein P1, respectively. The three other clones, smf-7, smf-40 and smf-61, are overexpressed in SMF-Ai. Clones smf-40 and smf-61 show significant homology with the human TB3-1 gene and the human fus gene respectively. The clone smf-7 has no significant homology with known sequences. We also analyzed the expression of these clones in other rat rhabdomyosarcoma cell lines (RMS-B and their clones) and in tumors obtained by injection of these cell lines into rats or nude mice. Smf-61 and smf-7 were the only clones with a differential expression pattern associated with the invasive or metastatic potential of all cell lines examined. A preliminary study of the expression of smf-7 and smf-61 in other cancer cell lines also showed mRNA expression in two human rhabdomyosarcomas and a human epidermoid carcinoma suggesting the existence of genes homologous to smf-7 and smf-61 clones in human cancers. Our findings suggest an association between the expression of smf-7 and smf-61 and invasive or metastatic potential of rhabdomyosarcoma cells.

Animals↗

PubMed2006

Multi-slice DCE-MRI data using P760 distinguishes between metastatic and non-metastatic rodent prostate tumors.

An intermediate molecular weight contrast agent P760 was used to investigate the ability of multi-slice dynamic contrast-enhanced MRI (DCE-MRI) to distinguish metastatic from non-metastatic rodent prostate tumors. Non-metastatic AT2.1 and metastatic AT3.1 prostate tumors originally derived from the Dunning prostate cancer model were implanted on the hind leg of Copenhagen rats. Multi-sliced DCE-MRI data were acquired on a SIGNA 1.5 T scanner and analyzed using a recently developed empirical mathematical model. The P760 multi-slice DCE-MRI data in combination with the empirical mathematical model successfully distinguished between metastatic and non-metastatic rodent prostate tumors. Specifically, fitting the data with the empirical model showed that metastatic tumors had significantly faster contrast media uptake (p<0.001) and slower washout rates (p<0.01) than non-metastatic tumors.

Algorithms↗

PubMed1995

Steady state and time-resolved fluorescence properties of metastatic and non-metastatic malignant cells from different species.

Steady state and time-resolved fluorescence spectroscopy were employed to study the fluorescence from non-metastatic, metastatic and non-tumorigenic cell lines from different species. Excitations at 310 nm and 350 nm were used to monitor tryptophan and reduced nicotinamide adenine dinucleotide (NADH) fluorescence respectively. Subtle and consistent differences were observed between different categories of cell lines. It was found that the tryptophan to NADH fluorescence intensity ratio is higher in metastatic cell lines than in non-metastatic and normal cell lines. The fluorescence decay of the tryptophan residue in different cell lines was best described by triple exponential kinetics, whereas the NADH fluorescence decay was best described by mainly double and, in some cases, triple exponential kinetics. The average fluorescence lifetimes for tryptophan were in the range 2.5-3.7 ns. The average lifetime of NADH was lower (by a factor of approximately three) in metastatic cells than in non-metastatic cells and this finding is consistent for cell lines from different origins (rat or human). Correcting the fluorescence intensity for the average fluorescence lifetime of each species and for the volume of each cell line, it was shown that the concentrations of tryptophan and NADH are consistently higher in malignant metastatic cancer cells than in non-metastatic cells.

Animals↗

PubMed2004

Metastatic carcinoma of the breast with tubular features: differences compared with metastatic ductal carcinoma of no specific type.

AIMS: To compare the metastatic pattern at presentation and the prognosis with metastases of 48 patients with carcinomas with tubular features (45 tubular mixed and three pure tubular) and 302 patients with tumours of ductal of no special type (DNST). MATERIALS AND METHODS: We carried out a retrospective study from a prospectively maintained database of all patients who developed metastatic disease from carcinoma of the breast in Nottingham, U.K., since 1997. We recorded site of first presentation with metastatic disease, radiological features, histological features and characteristics of the primary tumour. RESULTS: The group of patients with tubular features were older at metastatic presentation (63.9 years vs 59.6 years; P=0.012), had a longer disease-free interval (87 months vs 34 months: P<0.001) and a longer survival with metastases (P<0.002). This group were less likely to have liver metastases (23% vs 41%; P=0.028), in particular multiple liver metastases (50% vs 71%; P=0.015) than the patients with DNST. Other factors known to be associated with prolonged survival, such as low histological grade of the primary invasive tumour and positive oestrogen receptor (ER) status, were more common in the group of patients with tumours with tubular features (Grade 1: 33% vs 3%; Grade 2: 42% vs 25%; Grade 3: 25% vs 72%; P<0.001), (ER positivity 76% vs 52%; P=0.009). When patients with grade 2 tumours were compared, the age at metastatic presentation, disease-free interval and the presence of multiple liver metastases were still significantly different between the two groups. CONCLUSION: Patients with metastatic breast carcinoma with tubular features have a longer survival with metastases than patients with metastatic DNST carcinoma. This improved survival can be explained by better well-recognised prognostic features, such as metastatic site pattern, histological grade, ER status and disease-free interval.

Adenocarcinoma↗

PubMed1998

Generation of metastatic variants by transfection of a rat non-metastatic epithelial cell line with genomic DNA from rat prostatic carcinoma cells.

Prostate cancer is the second leading cause of male death from malignant disease in Europe and in the USA. Failure to prevent or eliminate metastatic dissemination is a fundamental problem underlying the current inadequate treatment of prostate cancer, and novel therapeutic strategies are required if this disease is to be successfully managed. No independent markers are yet available to predict the behaviour of any individual prostate cancer, particularly its potential to metastasize, and there is now an urgent prerequisite to identify and characterize genes specifically involved in determining the metastatic phenotype of prostate cancer cells before any biologically appropriate treatment modality can be devised. To identify DNA sequences that trophically promote the metastatic phenotype, we have established a new transfection assay with which to monitor activity of prostate cancer genomic DNA. Rat prostatic G and AT6.1 cell lines derived from the same original Dunning R3327 rat prostatic carcinoma exhibit, respectively, low- and high-metastatic phenotypes when grown in syngeneic Copenhagen rats. Rat mammary epithelial cell line 'Rama 37' derived originally from Wistar-Furth rats yields benign non-metastasizing adenomas when inoculated subcutaneously into syngeneic animals. In this report, the Rama 37 cell line is successfully used as the recipient cell-line for transfected DNA fragments extracted from rat prostatic carcinoma G and AT6.1 cells. New metastatic variants of Rama 37 cells have been generated. Enzymatically fragmented genomic DNA from rat metastatic prostate carcinoma cell lines was co-transfected together with plasmid pSV2neo into parental Rama 37 cells, followed by culture in the presence of Geneticin-G418 to select for the transfected cells. To enable subsequent identification of metastasis-promoting DNA sequences, the fragmented genomic DNA sequences were covalently attached to specifically engineered linker DNA molecules to flank the genomic DNA before transfection. Thereafter, the resulting transfectants were pooled and inoculated into mammary fat pads of female Wistar-Furth rats. Metastases produced by the transfectant cells in vivo were reestablished from secondary tumours and probed for the presence of the specific synthetic oligonucleotide sequences that flanked, and hence identified, the presence of the transfected DNA. These new metastatic cells are shown to provide a sensitive assay system with which to detect DNA sequences responsible for conveying the metastatic phenotype of prostate cancer when inoculated into syngeneic rats.

Animals↗

PubMed1984

Induction of the metastatic phenotype in a mouse tumor model by 5-azacytidine, and characterization of an antigen associated with metastatic activity.

The murine Lewis lung carcinoma is a long-term grafted tumor that, after subcutaneous inoculation, forms metastases to the lungs. Forty-two cell lines were established from a primary tumor site and 40 were established from lung metastatic foci. Cloned sublines were established from the original 82 lines, and 2 sublines among 405 were found to be tumorigenic but not metastatic (T+/M-), whereas the remaining 403 sublines were both tumorigenic and metastatic (T+/M+). The T+/M- phenotype was shown to be stable for greater than 2 yr. However, treatment of the T+/M- cell lines for 3 days with 3 microM 5-azacytidine resulted in reexpression of the metastatic phenotype in otherwise stable T+/M- lines. Also, 5-azacytidine treatment could result in loss of the metastatic phenotype in lines that had been stable T+/M+. The changes in tumorigenic and metastatic phenotypes were not associated with altered immunogenicity of the cells. Monoclonal antibodies were generated against T+/M+ cells, and one antibody ( M36D3 ) was found to bind only to T+/M+ cells. Reactivity of the antibody was found to co-vary with expression of the metastatic phenotype. The antigen recognized by M36D3 antibody thus seems to be associated with metastatic capability. The antigen was found by two-dimensional gel electrophoretic analysis to be a cellular protein of Mr approximately equal to 45,000 and pI approximately equal to 6.7.

Animals↗

PubMed2005

Proteomic analysis of differentially expressed proteins between metastatic and non-metastatic human colorectal carcinoma cell lines.

OBJECTIVES: To explore the expressions of metastasis-related proteins between metastatic LS174T and non-metastatic SW480 human colorectal carcinoma cell lines. METHODS: Two-dimensional gel electrophoresis (2-DE) was applied to separate the total proteins of cells. The silver-stained gels were analysed by 2-DE software Image Master 2D Elite. Selected differential protein spots were identified with peptide mass fingerprinting based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and database searching. RESULTS: The protein endothelial cell growth factor 1 (platelet-derived), rhotekin protein (RTKN), septin 1, cyclin-dependent kinase 1, sialic acid binding Ig-like lectin 11, tyrosinase-related protein-2, translin-like protein, and DNA directed RNA polymerase II polypeptide J-related gene isoform 2 appeared in metastatic but were not detected in non-metastatic cell lines, whereas integrin-linked kinase-associated protein phosphatase 2C isoform 2, MHC class I promoter binding protein, protein phosphatase 2A regulatory subunit B' (PR 53), carboxypeptidase A5, paired box transcription factor, zinc finger protein 79, and apolipoprotein B-48 were detected in non-metastatic but were absent in metastatic cell lines. In addition, cyclin fold protein 1 variant A and pre-B-cell leukemia transcription factor 1 were lowly expressed in the non-metastatic cell line and were significantly upregulated in the metastatic cell line. These identified proteins were involved in cell growth, motility, invasion, adhesion, apoptosis and tumour immunity, which is associated with distinct aspects of tumour metastasis. CONCLUSIONS: These data are valuable for the identification of differentially expressed proteins involved in human colorectal carcinoma carcinogenesis and metastasis.

Adenocarcinoma↗

PubMed1988

Metastatic capacity and intercellular communication between normal cells and metastatic cell clones derived from a rat mammary carcinoma.

Three highly metastatic clones and two weakly metastatic clones were obtained from a spontaneously arising mammary carcinoma in an SHR rat. The difference in their capacity to generate metastatic ability was recognized when the tumor cells were implanted s.c. but not when they were implanted i.v. This evidence possibly indicates that the difference in the metastatic capacity of these clones is caused by different potential for detachment from the primary site and for intravasation during the various steps of metastasis. There are no differences between highly and weakly metastatic clones with regard to their in vitro growth characteristics (doubling time, saturation density, plating efficiency, etc.), homotypic aggregation, and adhesiveness to plastic matrices and fibroblast monolayers. Therefore, we used a dye transfer method to examine the relationship between the metastatic capacity of tumor cells and the capacity of tumor cells to make junctional communication with normal fibroblasts. We found that the incidence of intercellular communication between weakly metastatic clone cells and fibroblasts (derived from normal s.c. tissues and tumor tissues) was significantly higher than that between highly metastatic clone cells and fibroblasts. These results suggest that junctional communication between tumor cells and normal fibroblasts may play a part in the early stage of cancer metastasis.

Animals↗

PubMed2003

Fine-needle aspiration cytology of metastatic nasopharyngeal carcinoma in cervical lymph nodes: comparison with metastatic squamous-cell carcinoma, and Hodgkin's and non-Hodgkin's lymphoma.

Our objective was to study the cytomorphological features of metastatic nasopharyngeal carcinoma (NPC) as compared to squamous-cell carcinoma (SCC) of nonnasopharyngeal origin, Hodgkin's lymphoma (HL), and non-Hodgkin's (NHL) lymphoma in the neck lymph nodes. The aim of this study was to find simple cytological criteria using routine stains that can help in differentiating between these entities. All fine-needle aspiration (FNA) smears of metastatic NPC, SCC, HL, and NHL from neck nodes available in our files were included in this study. Nodal disease was the first clinical manifestation in all cases of NPC, and all the lesions were of the nonkeratinizing type. The cytomorphological features of metastatic NPC, SCC, HL, and NHL have been described. Metastatic NPC and HL had a similar reactive lymphoid background, with eosinophils, plasma cells, and sometimes epithelioid-cell granulomas. The bizarre cells of NPC showed some resemblance to Reed-Sternberg cells of HL. However, the latter can be distinguished from the former on the basis of bulky, pale gray, vacuolated cytoplasm and vesicular nuclei with sharply demarcated prominent macronucleoli. In NPC, the neoplastic cells form distinct aggregates contrasting with the normal lymphoid cells in the background, which was different from the monotonous dispersed population of cells in NHL. Moreover, bizarre cells, prominent nucleoli, and the presence of plasma cells, eosinophils, and granulomas were not common features of NHL. The smears of metastatic SCC revealed keratinized malignant cells in all cases, while eosinophils and plasma cells were absent in the background. Plasma cells were seen intimately related to tumor cells in all cases of NPC. In conclusion, metastatic NPC can be differentiated from metastatic SCC of nonnasopharyngeal origin, HL, and NHL on the basis of simple nuclear and cytoplasmic features of malignant cells and their background. The presence of plasma cells intermingling with tumor-cell clusters is a good indicator of nasopharyngeal origin. On the other hand, a nasopharyngeal origin is unlikely in the presence of keratinized malignant cells.

Adolescent↗

PubMed2003

Statistical analysis of cytologic features useful in separation of metastatic urothelial carcinoma from other metastatic epithelial malignancies.

The identification of a site of origin and direction of differentiation for metastatic neoplasms is clinically important, but is often difficult purely by cytologic analysis of aspirated material. Cytologic separation of metastatic urothelial carcinoma (UC) from other moderate or poorly differentiated epithelial malignancies is difficult, with few cytologic criteria identified in the literature as valuable for this distinction. Several investigators have suggested that "cercariform cells" (CCs) are highly correlated with the presence of metastatic UC. We statistically analyzed the utility of 37 cytomorphologic features for the recognition of urothelial differentiation in a series of 26 metastatic UCs, 10 metastatic squamous cell carcinomas (SCCs), and 15 metastatic adenocarcinomas (ADCs). All specimens had been obtained from metastatic deposits in the lung, liver, lymph nodes, or soft tissues. Stepwise discriminate function analysis with all three diagnoses showed that the strongest discrimination could be made using the findings of waxy metaplastic cytoplasm, with significant increments in prediction added by analysis for (CCs) followed by spindle cells, multiple nucleoli, and columnar-shaped cells. The combination of these five variables accurately predicted 90% of all diagnoses, including 26 accurate diagnoses of UC, 9 accurate diagnoses of SCC, and 11 accurate diagnoses of ADC. CCs were present in highest numbers in UCs and present least frequently in cases of poorly differentiated ADC. While CCs were useful in the identification of UC, CCs occurred in a significant number of SCCs, limiting their diagnostic value as a single variable.

Adenocarcinoma↗

PubMed1984

The differential expression of H-2K versus H-2D antigens, distinguishing high-metastatic from low-metastatic clones, is correlated with the immunogenic properties of the tumor cells.

Two clones of the 3LL Lewis lung carcinoma, a low-metastatic clone A9 and a high-metastatic clone D122, were studied for MHC expression and immunogenic properties. Using monoclonal antibodies, we demonstrated that the A9 clone expresses both the H-2Kb and the H-2Db, whereas the D122 expresses only the H-2Db, and lacks the expression of the H-2Kb encoded molecules. Cells of the low-metastatic clone A9 grew progressively in syngeneic (C57BL/6J) or in F1 mice, but were rejected in allogeneic recipients. The high-metastatic D122 grew progressively in all mouse strains tested, yet metastases were formed only in syngeneic recipients. When H-2 recombinant mice were used, the A9 again manifested a significantly greater immunogenic potency than the metastatic D122, which grew in all 4 recombinants tested. Metastases, however, were formed in B10HTG and to a lesser extent in B10A(4R), thus indicating that metastasis formation is restricted by both C57BL background and H-2Db sub region. We subsequently tested whether the higher immunogenicity of the H-2Kb-positive A9 cells is expressed also in syngeneic mice, to examine whether this could account for its low metastatic phenotype. We found that immunization by A9 cells significantly inhibited the growth of a subsequent A9 graft and even of D122, yet D122 did not retard the growth of secondary D122 or A9 cells. The increased immunogenic effect was expressed also in the generation of syngeneic cytotoxic lymphocytes by A9 but not by D122 cells. We suggest that expression of H-2K molecules on the 3LL clones, immunogenicity and the metastatic phenotype are causally related in this system.

Animals↗

PubMed1993

Regulation of integrin-mediated adhesion to laminin and collagen in human melanocytes and in non-metastatic and highly metastatic human melanoma cells.

We compared integrin-mediated adhesion to extracellular matrix (ECM) components of cultured human melanocytes and 6 human melanoma cell lines with different metastatic capacities in nude mice. Cultured melanocytes and most melanoma cell lines adhered strongly to fibronectin (FN), whereas only highly metastatic cell lines adhered to laminin (LM), collagen type I (COI) and type IV (COIV). Adhesion to LM and CO could be blocked by anti-alpha 6 and anti-alpha 2 monoclonal antibodies (MAbs) respectively. This observation is consistent with the finding that expression of LM receptor alpha 6 beta 1 and LM/CO receptor alpha 2 beta 1 was low on melanocytes and non- or poorly metastatic cell lines, whereas these integrins were strongly expressed on highly metastatic cell lines. In addition, immunoprecipitation from [35S]-methionine-labeled cells demonstrated increased synthesis of alpha 6, alpha 2 and beta 1 in highly metastatic cell lines and immunohistochemistry showed expression of alpha 6 beta 1 and alpha 2 beta 1 only in xenograft lesions from highly metastatic cell lines. Furthermore, the observation that adhesion of melanocytes and non- or poorly metastatic cell lines could be stimulated with anti beta 1 MAbs demonstrates that these receptors, on these cells, are expressed in an inactive state. Our results suggest that alpha 2 beta 1 and alpha 6 beta 1 play a role in human melanoma metastasis in nude mice and demonstrate that interactions of these integrins with their ligands can be regulated at the level of surface expression and activation state of the receptor.

Animals↗

PubMed2003

Identification of differentially expressed genes in isogenic highly metastatic and poorly metastatic cell lines of R3230AC rat mammary adenocarcinoma.

Tumour metastasis occurs as a result of a cascade of events including alterations in the expression of various genes. The identification of such genes is essential to understanding formation of metastasis. In a previous study, highly metastatic (LN4.D6) and poorly metastatic (CAb.D5) cell lines were obtained from the rat mammary adenocarcinoma cell line R3230AC. Subtractive hybridization was used to identify differentially expressed genes between these two cell lines. We identified eight cDNA clones in CAb.D5 and six cDNA clones in LN4.D6 that were differentially expressed. One of the cDNA clones in each cell line had no homology with known sequences. Expression patterns of these differentially expressed genes were examined in a pair of rat mammary and prostate adenocarcinoma cell lines. Compared with cell lines examined, cDNA FF-10 was only expressed in CAb.D5; however, cDNA RB-8, RE-1, RF-5 were only expressed in the highly metastatic LN4.D6. No correlation was observed between expression patterns of the differentially expressed genes and metastatic potential of these cells. However, differential expression of genes, especially cytokeratins (CK8 and CK5) and collagens (III and IV) between highly metastatic and low metastatic rat mammary adenocarcinoma cell lines might initiate further investigation of these genes in metastatic process.

Adenocarcinoma↗