The expression of intermediate filament proteins is remarkably tissue-specific which suggests that the intermediate filament (IF) type(s) present in cells is somehow related to their biological function. However, in some cancers-particularly malignant melanoma and breast carcinoma, there is a strong indication that vimentin and keratin IFs are coexpressed, thus presenting as a dedifferentiated or interconverted (between epithelial and mesenchymal) phenotype. In this review, two in vitro models are presented which recapitulate the interconverted phenotype in human melanoma and breast carcinoma, and allow, for the first time, unique observations to be made with respect to the role of IFs in cancer progression. These studies have provided direct evidence linking overexpression of keratin IFs in human melanoma with increased migratory and invasive activity in vitro, which can be down-regulated by substituting dominant-negative keratin mutants. Overexpression of vimentin IFs in the breast carcinoma model leads to augmentation of motility and invasiveness in vitro, which can be transiently down-regulated by treatment with antisense oligonucleotides to vimentin. Additional experimental evidence suggests that the mechanism(s) responsible for the differential expression of metastatic properties associated with the interconverted phenotype rest(s) in the unique interaction, either direct or indirect, of IFs with specific integrins interacting with the extracellular matrix. In this review, we discuss the observations derived from the human melanoma and breast carcinoma models to address the hypothesis that the ability to coexpress vimentin and keratins confers a selective advantage to tumor cells in their interpretation of and response to signaling cues from the extracellular matrix. The ramifications of these observations are discussed with respect to the patholophysiology of the respective in situ tumors.
The objective of this study was to determine whether tumor-infiltrating B cells (TIL-B) of infiltrating ductal carcinoma (IDC) of the breast represent a tumor-specific humoral immune response. Immunohistochemical analysis of three Her-2/neu-negative IDC tumors from geriatric patients showed that TIL-B cluster in structures similar to germinal centers containing CD20+ B lymphocyte and CD3+ T lymphocyte zones with interdigitating CD21+ follicular dendritic cells, suggesting an in situ immune response. A total of 29, 31, and 58 IgG1 H chain clones was sequenced from the three IDC tumors, respectively. Intratumoral oligoclonal expansion of TIL-B was demonstrated by a preponderance (45–68%) of clonal B cells. In contrast, only 7% of tumor-draining lymph node and 0% of healthy donor PBL IgG H chains were clonal, consistent with the larger repertoires of node and peripheral populations. Patterns and levels of TIL-B IgG H chain somatic hypermutation suggested affinity maturation in intratumoral germinal centers. To examine the specificity of TIL-B Ig, a phage-displayed Fab library was generated from the TIL-B of one IDC tumor. Panning with an allogeneic breast cancer cell line enriched Fab binding to breast cancer cells, but not nonmalignant cell lines tested. However, panning with autologous tumor tissue lysate increased binding of Fab to both tumor tissue lysate and healthy breast tissue lysate. These data suggest an in situ Ag-driven oligoclonal B cell response to a variety of tumor- and breast-associated Ags.
Dendritic cell (DC) immunotherapy has shown significant promise in animal studies as a potential treatment for cancer. Its application in the clinic depends on the results of human trials. Here, we review the published clinical trials of cancer immunotherapy using exogenously antigen-exposed DCs. We begin with a short review of general properties and considerations in the design of such vaccines. We then review trials by disease type. Despite great efforts on the part of individual investigative groups, most trials to date have not yielded data from which firm conclusions can be drawn. The reasons for this include nonstandard DC preparation and vaccination protocols, use of different antigen preparations, variable means of immune assessment, and nonrigorous criteria for defining clinical response. While extensive animal studies have been conducted using DCs, optimal parameters in humans remain to be established. Unanswered questions include optimal cell dose, use of mature versus immature DCs for vaccination, optimal antigen preparation, optimal route, and optimal means of assessing immune response. It is critical that these questions be answered, as DC therapy is labor- and resource-intensive. Cooperation is needed on the part of the many investigators in the field to address these issues. If such cooperation is not forthcoming, the critical studies that will be required to make DC therapy a clinically and commercially viable enterprise will not take place, and this therapy, so promising in preclinical studies, will not be able to compete with the many other new approaches to cancer therapy presently in development. Trials published in print through June 2003 are included. We exclude single case reports, except where relevant, and trials with so many variables as to prevent interpretation about DC therapy effects.
We conclude that endothelial progenitor cells can be isolated from human adult peripheral and umbilical cord blood and developed into EC cultures as a source of cells for vascular graft seeding and gene therapy.
Metastasis of melanoma to the central nervous system (CNS) remains one of the major barriers to successful treatment of this disease. Available treatment modalities are of limited clinical efficacy. This problem is compounded by the presence of the blood-brain barrier (BBB), an important consideration in the development of new therapeutic agents. Only in animal models can the dual properties of experimental tumours and the BBB be explored in one system. A variety of rodent models have been developed, utilizing both murine and human melanoma cell lines. These models have highlighted the complex biology of cerebral metastasis, involving apparent disease progression through the selection of subclones at each stage, eventually leading to disease in the brain. As demonstrated in a number of animal studies, different subpopulations of metastatic melanoma cells are likely to be responsible for parenchymal and leptomeningeal CNS disease. In addition, these animal systems have been used to demonstrate the potential efficacy of new chemotherapeutic drugs, radiation treatments and immunotherapeutic approaches for the treatment of melanoma brain metastasis. Key biological questions remain to be answered. In particular, the molecular and cellular mechanisms responsible for establishing cerebral melanoma must be clearly delineated. Several molecules, including vascular endothelial growth factor (VEGF) and integrins, appear to play important, but not definitive, roles. Other, as yet undefined, molecules appear to be critical. The identification of these factors in experimental models, with confirmatory studies in humans, will expand our understanding of cerebral melanoma and provide valuable new therapeutic targets for intervention in this difficult clinical problem.
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