No abstract

Squamous cell carcinoma (SCC) of the head and neck is the sixth most frequent cancer worldwide. The survival rate is among the lowest of the major cancers and has not improved significantly in the past two decades. Extensive local invasion and regional lymph node metastasis are, in large part, responsible for the poor clinical outcome of these tumors. Keratin intermediate filaments are the most abundant cytoskeletal proteins in SCCs and regulate the migration of normal and transformed epithelial cells. Previous studies have shown that expression of the 40-kDa keratin K19 is dysregulated in SCCs arising from oral epithelium. Immunohistochemical experiments demonstrated that, while normal epithelium and dysplastic lesions expressed abundant K19 protein, invasive SCCs exhibited a patchy or negative staining pattern. We subsequently determined that K19 expression was consistently downregulated in seven SCC lines compared with normal epithelium. We therefore wanted to determine if K19 downregulation affected the invasive phenotype of these cells. We found that SCC lines which do not express K19 are significantly more invasive in vitro than those which retain expression of this gene. Stable expression of the K19 cDNA in K19 negative cell lines altered cell morphology and intercellular adhesiveness, and significantly decreased the number of cells able to migrate through a reconstituted basement membrane. Reduced invasiveness was not due to decreased metalloproteinase activity in the K19-expressing clones. We conclude that K19 overexpression in oral SCCs decreases their invasive potential by diminishing migratory capability.

Human fibroblasts were subjected to nutritionally induced GI block, followed by release and subsequent entry into S phase, and exposed to nontoxic concentrations of carcinogens in early S phase. Cell transformation occurred as determined by early morphologic cell alterations, anchorage-independent colony formation, cell invasiveness, and augmentation of Ab 376 human malignancy-specific cell-surface antigenic determinant. Methylazoxymethanol acetate was the most potent transforming agent at doses that were negative in toxicity tests. Benzamide (10 FM intracellular concentration), a specific inhibitor of poly(ADPribose) polymerase, prevented transformation in a cell cycle-specific manner, maximal prevention coinciding with early S phase, also characteristic of maximal susceptibility to transformation. Neither an interference of carcinogen deoxyguanosine nucleoside adduct formation nor a chemical reaction between benzamide and carcinogens was detected. Methylazoxymethanol acetate at transforming but nontoxic dose partially inhibited poly(ADP-ribosyl)ation to about the same extent as benzamide. However, simultaneous exposure of cells to both agents in early S phase, resulting in the prevention of transformation, augmented poly(ADPribosyl)ation above the controls. Enzymatic activities ran parallel with the formation of DNA-associating polymer-nonhistone protein adducts that are assumed to regulate the physiological function of chromatin at the structural level.A significant increase in poly(ADP-ribosyl)ation of nonhistone proteins was found in an early precancerous state of hamster liver (1) and in regenerating rat liver (2), suggesting that cellular regeneration may be a common reason for the accelerated enzymatic rates. Cellular regeneration is known to augment the number of cells in S phase and this has been correlated with the facilitation of neoplastic transformation in organs (3) and in cultured C3H/101/3 CL8 mouse fibroblasts (4). Poly(ADP-ribosyl)ation also exhibits a cell cycle-dependent oscillation, a maximum coinciding with S phase after a release of G1 block (5). These observations tend to suggest an as yet undefined connection between (poly ADP-ribosyl)ation, cell cycle, and neoplastic transformation.Ontogenic development (6), the effect of developmental hormones (7-9), and differentiation (10) also coincide with changes in rates of poly(ADP-ribosyl)ation of mainly nonhistone proteins (11, 12) that are thought to regulate selective gene expression (13). Identification of poly(ADP-ribose) as a unique nucleic acid (14, 15) that is covalently bound to presumably DNA-associated proteins may provide a molecular model of chromatin regulation. Ionic environment-dependent helical polymer chains of poly(ADP-ribose) (15) may act as crosslinking agents between regulatory proteins and, depending on their nature and localization, could alter chromatin conformations, expressed as karyological changes that accompany the cell cycle in normal and malignant cells (16,17). The poly(ADP-ribosyl)ation-dependent var...

Prostaglandins are synthesized from eicosa-8,11,14-trienoic acid and eicosa-5,8,11-14-tetraenoic acid by smooth muscle cell cultures from guinea pig aorta. Production is inhibited by indomethacin. The precursor fatty acids and their prostaglandin derivatives inhibit proliferation of the cell cultures. The relative availability of fatty acids for prostaglandin biosynthesis may represent a control mechanism for cell proliferation.

There is only indirect evidence at present to suggest a role for PRL in either the genesis or progression of human breast cancer. Here, we report the results of experiments in primary cultures of breast tumor cells from a hyperprolactinemic breast cancer patient who had an elevated mean 24-h PRL concentration but a normal diurnal variation of PRL release. The effects of PRL and GH on the growth of the dispersed cells from the breast tumor was evaluated in monolayer culture using a recently developed microculture technique. Pharmacological quantities of GH produced significant increases in the number of population doublings of the breast tumor cells. Also, PRL concentrations present in the patient's circulation were demonstrated to significantly increase the number of population doublings of the breast tumor cells obtained in primary cultures. Thus, physiological concentrations of PRL stimulated the growth of breast tumor cells from this premenopausal patient.