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PubMed1990

Nuclear DNA measurements of metastatic melanoma by a computerized digital imaging system.

To determine the extent of nuclear DNA abnormalities and their relationship with prognosis of stage II malignant melanoma, metastatic melanomas in lymphadenectomy specimens of 22 patients were studied by a computerized digital imaging system. The DNA ploidy pattern was aneuploid in 86% of the cases and tetraploid in the remaining 14%. In metastatic melanomas, there was a single clone in one third of patients and multiple clones in the remaining two thirds. Poor survival rate was associated with multiple clones and greater than 30% of mean coefficient of variation of DNA content. With tumor progression stem-cell lines often became heterogeneous with the development of multiple clones and widespread DNA values. These abnormalities, determined by nuclear DNA ploidy analysis, provide useful prognostic information.

DNA, Neoplasm↗

PubMed2006

VEGF and BMP expression in mouse osteosarcoma cells.

Osteosarcoma is the most common primary bone malignancy. Despite improvements in therapy, approximately 30% of patients experience pulmonary metastasis. Expression of several growth factors, including VEGF and BMPs, has been implicated in tumor progression and metastatic potential. We hypothesized increased metastatic potential of mouse osteosarcoma cells positively correlates with the expression of VEGF and BMPs. We studied the expression patterns of these growth factors in two murine osteosarcoma cell lines with varying degrees of metastatic potential: K7M2 (highly metastatic) and K12 (minimally metastatic). Expression of VEGF and BMP2 were higher in the metastatic K7M2 cell line. We also investigated the effects of the BMP antagonist noggin on osteosarcoma growth characteristics in vitro. We noted decreased motility, altered morphology, and increased cell death in the highly metastatic K7M2 cell line. Less metastatic K12 cells showed substantial cell death without clear alteration of motility or morphology. These data suggest BMP2 expression may be an important factor in osteosarcoma metastasis and noggin administration theoretically could block its actions. Inhibition of BMPs and VEGF should be investigated further as a possible strategy for decreasing the incidence of pulmonary metastases in osteosarcoma.

Animals↗

PubMed1992

The morphologic characteristics of tumor blood vessels as a marker of tumor progression in primary human uveal melanoma: a matched case-control study.

Nine morphologic patterns of tumor vessels were identified in eyes removed for ciliary body or choroidal melanoma by the examination of tissue sections stained with fluorescein-conjugated Ulex europaeus I using laser scanning confocal microscopy. This technique also highlights intravascular tumor invasion. Each of these nine morphologic patterns of tumor vessels also may be demonstrated by a modification of the periodic acid-Schiff reaction, viewed with a green narrow band pass filter, but this modified histochemical technique does not accurately identify intravascular tumor invasion. Most tumors have a heterogeneous distribution of vascular patterns. Melanomas in two groups of 20 tumors each were matched by tumor size and location (one group of tumors from patients who survived at least 15 years free of metastatic melanoma after enucleation and one group of tumors from patients who died of metastatic melanoma). A matched case-control analysis indicates that the presence of at least one closed vascular loop in a uveal melanoma is the most significant vascular pattern associated with death from metastatic melanoma after enucleation. Closed loops are associated with other histologic features that are predictive of an unfavorable outcome after enucleation: epithelioid cells and mitotic figures. In this preliminary study the formation of closed vascular loops is a marker of tumor progression in ciliary body and choroidal melanomas.

Adult↗

PubMed2000

Tumor cell adhesion of human colon carcinoma cells with different metastatic properties to extracellular matrix under dynamic conditions of laminar flow.

PURPOSE: Shear forces have an important influence on cell adhesion and other cellular functions, and malignant cell lines appear to possess different adhesive properties under static and dynamic conditions. Thus, we analyzed human colon carcinoma cell adhesion under dynamic conditions and examined the interactions of HT-29 colon carcinoma cells of different metastatic properties with various immobilized ECM components. METHODS: Wall shear adhesion threshold (WSAT), dynamic adhesion rate (DAR), and adhesion stabilization rate (ASR) were compared between the cell lines using dynamic conditions in a laminar flow chamber by decreasing the flow (wall shear stress) of cell suspensions. Patterns of cell adhesion under dynamic conditions were compared to adhesive interactions in static microtiterplate assays. RESULTS: Poorly metastatic HT-29P cells adhered six times more than highly metastatic cells to type I collagen under laminar fluid flow, whereas only highly metastatic HT-29LMM showed adhesive interactions with fibronectin under static and dynamic conditions. High rates of cell adhesion to collagen IV were found under static, but not under dynamic, conditions. CONCLUSIONS: Although poorly and highly metastatic HT-29 cells express similar patterns of integrins, they differ in their adhesive properties to ECM components under static and dynamic conditions. Hydrodynamic shear forces appear to influence adhesive properties of HT-29 cells, and differences between dynamic and static cell adhesion were found.

Carcinoma↗

PubMed1991

Cutaneous and subcutaneous leiomyosarcoma: a clinicopathological review of 14 cases with reference to antidesmin staining and nuclear DNA patterns studied by flow cytometry.

Among 14 patients (11 female and three male) with cutaneous and subcutaneous leiomyosarcomas, metastatic spread occurred in six of the 13 patients with adequate follow-up. The tumours were classified with regard to tumour grade, number of mitotic figures per 10 high-power fields, reactivity to antidesmin antibodies, and DNA pattern as assessed by flow cytometry. Antidesmin antibody staining was present in only six cases and seemed to be less common in the higher-grade tumours. The DNA pattern was aneuploid in five cases and non-classifiable in one case; all of these cases had metastatic spread. None of the eight remaining diploid cases had metastatic spread. DNA content was a strong predictor of metastatic potential.

Adolescent↗

PubMed1999

Role of integrins in cancer: survey of expression patterns.

Tumor cells are characterized by uncontrolled growth, invasion to surrounding tissues, and metastatic spread to distant sites. Mortality from cancer is often due to metastasis since surgical removal of tumors can enhance and prolong survival. The integrins constitute a family of transmembrane receptor proteins composed of heterodimeric complexes of noncovalently linked alpha and beta chains. Integrins function in cell-to-cell and cell-to-extracellular matrix (ECM) adhesive interactions and transduce signals from the ECM to the cell interior and vice versa. Hence, the integrins mediate the ECM influence on cell growth and differentiation. Since these properties implicate integrin involvement in cell migration, invasion, intra- and extra-vasation, and platelet interaction, a role for integrins in tumor growth and metastasis is obvious. These findings are underpinned by observations that the integrins are linked to the actin cytoskeleton involving talin, vinculin, and alpha-actinin as intermediaries. Such cytoskeletal changes can be manifested by rounded cell morphology, which is often coincident with tumor transformation via decreased or increased integrin expression patterns. For the various types of cancers, different changes in integrin expression are further associated with tumor growth and metastasis. Tumor progression leading to metastasis appears to involve equipping cancer cells with the appropriate adhesive (integrin) phenotype for interaction with the ECM. Therapies directed at influencing integrin cell expression and function are presently being explored for inhibition of tumor growth, metastasis, and angiogenesis. Such therapeutic strategies include anti-integrin monoclonal antibodies, peptidic inhibitors (cyclic and linear), calcium-binding protein antagonists, proline analogs, apoptosis promotors, and antisense oligonucleotides. Moreover, platelet aggregation induced by tumor cells, which facilitates metastatic spread, can be inhibited by the disintegrins, a family of viper venom-like peptides. Therefore, adhesion molecules from the integrin family and components of angiogenesis might be useful as tumor progression markers for prognostic and for diagnostic purposes. Development of integrin cell expression profiles for individual tumors may have further potential in identifying a cell surface signature for a specific tumor type and/or stage. Thus, recent advances in elucidating the structure, function, ECM binding, and signaling pathways of the integrins have led to new and exciting modalities for cancer therapeutics and diagnoses.

Apoptosis↗

PubMed2003

Inhibin alpha distinguishes hemangioblastoma from clear cell renal cell carcinoma.

Inhibin alpha subunit (inhibin A) expression in hemangioblastomas has not been previously reported in the literature. We analyzed the expression of inhibin A in 25 hemangioblastomas from 22 patients. Eleven cases were from 8 patients with von Hippel-Lindau disease, and these tumors were multicentric and/or recurrent. The remaining 14 cases from 14 patients were sporadic. The male-to-female ratio was 8:3, and the age at presentation ranged from 19 to 78 years (mean 35 years; median 45 years). Eighteen tumors were located in the cerebellum/posterior fossa, 1 in the medulla, 1 in the occipital lobe, and 5 in the spinal cord. Four metastatic renal cell carcinomas in brain, 10 renal cell carcinomas from 8 patients with von Hippel-Lindau disease, and 5 sporadic clear cell renal cell carcinomas were also included. Two patients with von Hippel-Lindau disease had both renal cell carcinoma and hemangioblastoma. The stromal cells of all 25 cases of hemangioblastoma expressed inhibin A. Strong, moderate, and weak cytoplasmic immunoreactivity was noted in 17, 5, and 3 cases, respectively. In contrast, none of the 19 renal cell carcinomas, primary as well as metastatic, expressed inhibin A. There was no difference in the inhibin A staining pattern between the sporadic hemangioblastoma and those associated with VHL. These findings demonstrate inhibin A to be a useful marker in distinguishing hemangioblastoma from metastatic clear cell renal cell carcinoma. While the diagnostic importance is evident, the pathophysiology of inhibin A expression by the stromal cells of hemangioblastoma remains unknown and further investigation is required.

Adenocarcinoma, Clear Cell↗

PubMed2004

Metastatic basal cell carcinoma: rapid symptomatic response to cisplatin and paclitaxel.

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer in the community, although it rarely metastasizes. The literature reports less than 100 patients who have received chemotherapy for metastatic BCC. A further case of this rare disease is reported here. The pattern of disease in the reported patient was similar to that described in the literature, but the patient experienced a long period with untreated metastatic disease compared with that in the literature. METHOD: The patient was treated with cisplatin in combination with paclitaxel. Literature review suggests this to be the first report of this combination. RESULTS: Rapid symptomatic response was achieved though late neurotoxicity occurred. CONCLUSION: This regimen is an active combination for the rare patient with metastatic BCC. The combination of carboplatin and paclitaxel causes less neurotoxicity and may therefore be a superior regimen.

Antineoplastic Agents↗

PubMed1976

Tissue T and B cell infiltration of primary and metastatic cancer.

Immunofluorescent techniques were utilized to identify the types of infiltrating lymphocytes adjacent to human malignant tumors arising from a wide range of anatomic sites. 24 of 29 primary tumors and 5 of 8 metastatic lesions showed varying degrees of lymphocytic infiltration. T cells predominated in the infiltrates in primary tumors (mean 80%, range 50-100%) and this pattern was evident regardless of anatomic site or the presence or absence of metastatic spread. By contrast, B cells predominated at the margins of three of five tumor metastases. Mononuclear cells bearing the Fc receptor were not a prominent component of the infiltrates associated with either primary tumors or metastases, but tumor cell binding of fluoresceinated IgG aggregates was observed in 12 of 29 primary tumors. A significant reduction in peripheral blood T cell numbers occurred in a third of the patients studied. This decrease was not clearly related either to the extent of local tumor T cell infiltration or to the presence of disseminated disease. These preliminary findings provide a descriptive analysis of the local and systemic distributions of immunocompetent cells in cancer.

Adult↗

PubMed1994

Pancreatic trypsinogen and cathepsin B in human pancreatic carcinomas and associated metastatic lesions.

Expression of pancreatic trypsinogen and cathepsin B in 23 surgically resected pancreatic ductal adenocarcinomas was evaluated immunohistochemically, using a monoclonal antibody against human pancreatic trypsinogen and a polyclonal antibody against human cathepsin B. Fifteen of 20 invasive tubular adenocarcinomas (75%) expressed pancreatic trypsinogen in a coarse granular pattern located in the supranuclear cytoplasm of the carcinoma cells. In addition, metastatic lesions, including those in peripancreatic lymph nodes and neural plexuses, expressed pancreatic trypsinogen. In contrast, three intraductal (non-invasive) papillary adenocarcinomas did not express pancreatic trypsinogen. Cathepsin B expression was recognised in 14 of 20 invasive tubular adenocarcinomas (70%) in a fine granular pattern located diffusely in the cytoplasm of the carcinoma cells, while none of the three intraductal papillary adenocarcinomas had detectable cathepsin B. These findings suggest that pancreatic invasive ductal adenocarcinomas express pancreatic trypsinogen and cathepsin B immunoreactive peptides, raising the possibility that pancreatic trypsinogen and cathepsin B may act independently of each other in the process of carcinoma invasion and metastasis, like other different classes of proteases involved in the proteolytic modification of the matrix barrier.

Adult↗

PubMed2003

Molecular markers in ductal carcinoma in situ of the breast.

Gene expression patterns in ductal carcinoma in situ (DCIS), and in invasive, and metastatic breast tumors were determined using serial analysis of gene expression (SAGE). We used mRNA in situ hybridization to examine gene expression at the cellular level and immunohistochemistry on tissue microarrays to determine association between gene expression patterns and histopathologic characteristics of the tumors. We found that that the most dramatic transcriptome change occurs at the normal to DCIS transition, while there is no clear universal "in situ" or "invasive" tumor molecular signature. From the 16,430 transcripts analyzed, we identified only 5 and 11 that were preferentially up-regulated in DCIS and invasive tumors, respectively. The majority of invasive cancer specific SAGE tags correspond to novel genes. The genes we identified may define biologically and clinically meaningful subgroups of DCIS with a high risk of progression to invasive disease.

Breast Neoplasms↗

PubMed1995

Hepatic leiomyosarcomas: CT features with pathologic correlation.

The purpose of this study was to determine the computed tomographic (CT) features of hepatic leiomyosarcoma and to correlate them with pathologic findings. CT examinations of 15 patients with pathologically proven leiomyosarcoma of the liver were retrospectively reviewed. Three patients had primary leiomyosarcoma of the liver and 12 patients had 43 distinct hepatic metastases originating from a primary gastrointestinal (n = 8), uterine (n = 2) or retroperitoneal (n = 2) leiomyosarcoma. In the 11 patients who had partial hepatic resection or surgical biopsy of their tumors, a correlation was made between CT imaging and pathologic findings. Primary leiomyosarcomas showed heterogeneous enhancement; two displayed internal and peripheral enhancement, and one showed peripheral enhancement with a pseudocystic pattern (i.e. enhancing thick wall with internal nonenhancing low attenuation area). Leiomyosarcomas metastatic to the liver were homogeneous, showing no or moderate enhancement (10 of 43 metastases, 23%) or heterogeneous and predominantly peripheral enhancement (33 of 43 metastases, 77%). A pseudocystic pattern was seen in 13 of the 43 metastases (30%). Homogeneous tumors were made of smooth fibrous-like tissue without area of necrosis. Heterogeneous tumors contained varying degrees of necrosis and hemorrhage or gelatinous tissue. We found that primary and secondary hepatic leiomyosarcomas of the liver can exhibit different features. A pseudocystic pattern is uncommon. Furthermore, purely cystic tumors were not seen in our series.

Adult↗

PubMed1999

A fluorescent orthotopic bone metastasis model of human prostate cancer.

Here, we report a fluorescent spontaneous bone metastatic model of human prostate cancer developed by surgical orthotopic implantation of green fluorescent protein (GFP)-expressing prostate cancer tissue. Human prostate cancer PC-3 cells were transduced with the pLEIN expression retroviral vector containing the enhanced GFP and neomycin resistance genes. Stable GFP high-expression PC-3 clones were selected in vitro with G418, which were then combined and injected s.c. in nude mice. For metastasis studies, fragments of a single highly fluorescent s.c. growing tumor were implanted by surgical orthotopic implantation in the prostate of a series of nude mice. Subsequent micrometastases and metastases were visualized by GFP fluorescence throughout the skeleton, including the skull, rib, pelvis, femur, and tibia The central nervous system, including the brain and spinal cord, was also involved with tumor, as visualized by GFP fluorescence. Systemic organs, including the lung, plural membrane, liver, kidney, and adrenal gland, also had fluorescent metastases. The metastasis pattern in this model reflects the bone and other metastatic sites of human prostate cancer. Thus, this model should be very useful for the study and development of treatment for metastatic androgen-independent prostate cancer.

Animals↗

PubMed1990

Relationship of 4F2 antigen with local growth and metastatic potential of squamous cell carcinoma of the larynx.

The 4F2 antigen is a cell-membrane glycoprotein which arises early in the G0-G1 phases of the cell cycle. This molecule is present in all established human cell lines and most malignant human cells. The authors used an indirect immunophosphatase method to study 50 squamous cell carcinomas of the larynx and ten lymph-node metastases, corresponding to six primary tumors, for 4F2 expression. The tumors showed several patterns of 4F2 staining which were correlated with different behaviors and prognoses of the neoplasms. Three different patterns (no staining, peripheral staining, and diffuse 4F2 expression) are described as are their relationships with metastatic behavior of the carcinomas. Tumors with metastases were found only in the third group (P = 0.0001). These results led to the following conclusions: (1) the 4F2 antigen is present in squamous cell carcinomas; (2) its distribution reflects the tumor-spreading pattern; and (3) it correlates with differentiation and metastatic behavior.

Antibodies, Monoclonal↗

PubMed1998

CT of calcified liver metastases in colorectal carcinoma.

PURPOSE: To assess the incidence, characteristics and prognostic significance of calcification within colorectal hepatic metastases. MATERIALS AND METHODS: A retrospective analysis of CT in 265 patients with locally advanced or metastatic cancer was performed. Four groups were defined: (a) calcification within liver metastases prior to therapy, (b) noncalcified liver metastases with development of calcification on therapy, (c) noncalcified liver metastases, and (d) advanced local tumour without liver metastases. The number of calcified deposits in each patient was documented. A marker lesion was analysed for character, distribution and percentage of calcification. Survival between the four groups was compared. RESULTS: Twenty-nine (11%) patients had calcified liver metastases at presentation and 10 (4%) developed calcification during chemotherapy. Analysis of a marker lesion showed that the most frequent characteristic was fine calcification with a variable distribution. The most frequent change on treatment was alteration in the extent of calcification. Calcification developing on treatment was usually central. There was no difference in survival between groups 1, 2 and 3, but groups 1, 2 and 3 had a shorter survival than group 4. CONCLUSION: Calcification of liver metastases shows a variable pattern and may develop or change during therapy. Liver metastatic calcification may not carry any prognostic significance in colorectal cancer.

Antimetabolites, Antineoplastic↗

PubMedDate not supplied

Changes in the zonation of lactate dehydrogenase activity in lobules of rat liver after experimentally induced colon carcinoma metastases.

Visualization of lactate dehydrogenase (LDH) activity with Neotetrazolium as final electron acceptor under anaerobic conditions and an incubation medium containing polyvinyl alcohol showed that under normal physiological conditions a zonal distribution of LDH activity is present in the liver lobule of male rats. Periportal hepatocytes contain more LDH activity than pericentral hepatocytes. This difference is due to the role of LDH both in gluconeogenesis (periportal cells) and glycolysis (pericentral cells). In livers containing metastases from colon carcinoma, areas of the parenchyma which are not affected by tumour growth maintain such zonation in the lobule, whereas areas close to metastatic foci show increased activity which is distributed uniformly over the lobule. This change may be explained by a Cori's cycle-like relationship between malignant cells and the surrounding hepatocytes due to glucose consumption and lactate production by the tumour cells. Within the metastatic foci, a zonation of LDH activity was also observed. Malignant cells close to the edge of the tumours contained the lowest activity, whereas activity increased inwards. Cancer cells directly surrounding necrotic areas showed the highest activity. Such patterns are in line with increasing anaerobic glycolysis towards the inner metastatic regions. Anaerobic glycolysis supplies limited amounts of ATP with concomitant lactate production but also large amounts of metabolites for RNA, DNA, lipid and complex carbohydrate synthesis. Lactate that is produced by the metastases induces adaptive changes in surrounding hepatocytes to convert this excess of lactate effectively.

1,2-Dimethylhydrazine↗

PubMed1991

[Duck hepatitis B virus DNA in multiple primary cancers and metastatic tumors in duck liver].

Duck hepatitis B virus (DHBV) DNA was detected in both multiple primary cancers and intrahepatic metastatic tumors in duck liver by Southern blot technique. Among 7 ducks with multiple primary tumors in the liver, the banding pattern of integrated DHBV DNA in different tumors was identical in 3 animals but different in 2. One duck showed a similar hybridization pattern in different tumor nodules and the remaining one was negative for DHBV DNA. Integrated DHBV DNA was also identified in one duck with metastatic tumor in the lung, in which the hybridization pattern was the same as that of the primary hepatocellular carcinoma. The presence of the same distinct hybridization bands in various tumor nodules indicated that they may arise from the same clone of neoplastically transformed cell. Different hybridization bands showed that tumors may arise from different clones. The results suggest that hybridization pattern of hepatic carcinoma with viral DNA probe could be used as a clone marker of transformed cells to distinguish multiple primary hepatic cancers from intrahepatic metastasis.

Adenoma, Bile Duct↗

PubMed1995

Squamous cell carcinoma of the uterine cervix. Patterns of thoracic metastases.

RATIONALE AND OBJECTIVES: Distant metastasis of cervical cancer, once considered rather uncommon, has become more common in recent years because of longer survival of the patients. The purpose of this study is to evaluate the radiographic patterns of its thoracic metastases correlating with the pathways of metastatic tumor spread. METHODS: The conventional radiographs (62 cases), thoracic computed tomography images (20 cases), and medical records of 62 patients with advanced squamous cell carcinoma of the uterine cervix with thoracic metastases who died of extensive disease and its complications during a recent 5-year period were reviewed retrospectively. RESULTS AND CONCLUSIONS: In addition to the most typical pattern of multiple pulmonary nodules (71%), mediastinal and hilar lymphadenopathy (32%) and pleural metastases (27%) were frequently observed. Rare findings included bone metastases (6%), endobronchial obstruction (5%), and lymphangitic carcinomatosis (3%). The mechanisms of metastasis in relation to the above manifestations are proposed.

Adult↗