Cancer cells (Cold Spring Harbor, N.Y. : 1989)最新文献

Progression from a treatment-sensitive to a treatment-resistant tumor state is a virtually universal phenomenon in patients with small-cell lung carcinoma (SCLC). In such individuals, this tumor progression may involve transitions from a SCLC to a non-SCLC lung cancer phenotype. We are investigating the cell and molecular biology aspects of these transitions and have derived a cell culture model of one such change, oncogene-induced transition of SCLC to the large-cell undifferentiated lung cancer phenotype. Here we discuss the potential implication of this model for understanding the cell lineage and molecular events regulating normal bronchial epithelial cell differentiation and their relationships to the histogenesis and behavior of lung cancers.

Exposure to solar ultraviolet (UV) radiation is recognized as an important cause of skin cancer. The carcinogenic effects of UV radiation have been attributed almost entirely to wavelengths in the mid-range (UVB, 290-320 nm). However, the development of potent UVB sunscreens has allowed individuals to increase the length of time that they spend sunbathing and, as a consequence, they may be exposed to massive doses of longwave UV radiation (UVA, 320-400 nm). There is now much evidence to suggest that UVA acts to promote tumors that have been initiated by UVB. This review considers possible mechanisms by which UVA promotes tumorigenesis. Evidence is presented which suggests that UVA acts through modulation of protein kinase C.

Oxidants, which are generated by multiple pathways in mammalian organisms, may be natural carcinogens and contribute to several stages of malignant transformation. Active oxygen released by inflammatory phagocytes and more stable "clastogenic factors" can induce mutations and chromosomal aberrations in neighboring target cells. These oxidant-induced DNA sequence changes, though rare, may affect the activities of proto-oncogenes and suppressor genes. In addition, oxidants can promote cell growth. Like polypeptide growth factors they activate kinases. Because they break DNA, they also induce the poly ADP-ribosylation of chromosomal proteins. Both phosphorylation and poly ADP-ribosylation appear to participate in the transcriptional induction of the growth-related proto-oncogene c-fos. Growth stimulation by oxidants is modulated by the cellular antioxidant defenses. Maximal growth promotion is observed when cells are protected from excessive toxicity but still maintain a sufficient oxidant signal for the induction of growth-competence genes.

There has been a long-standing clinical impression that tumor grow more slowly in elderly patients, but, because of confounding variables, this impression has been difficult to substantiate by epidemiologic data. Animal models offer a way to explore the relationship between host age and tumor growth under more controlled conditions. Our studies with murine B16 melanoma xenografts, discussed here, show that tumor growth and spread is in fact reduced in older animals and suggest that age-associated changes in immune function may be partially responsible.

Transforming growth factor-alpha (TGF-alpha) is a 50-amino-acid mitogenic peptide that is structurally and, in some cases, functionally related to members of the epidermal growth factor (EGF) family of peptides. TGF-alpha is initially synthesized as a high-molecular-weight, glycosylated, membrane-associated precursor of approximately 160 amino acids. The low-molecular-weight TGF-alpha peptide as well as the precursor are biologically active in a number of systems and can function as transforming proteins when overexpressed. TGF-alpha binds to and activates the EGF receptor, and TGF-alpha and the EGF receptor are coexpressed in a number of human and rodent tumors and tumor cell lines--which suggests that TGF-alpha can function as an autocrine or paracrine growth factor. TGF-alpha is transiently expressed in some fetal and adjacent maternal tissues during development and is also expressed in a number of adult tissues; this pattern of expression suggests that the growth factor is involved in several distinct physiological functions.

Cells respond to proliferative signals generated by growth factors and oncogenes with a complex array of biochemical and physiological events, culminating in DNA synthesis and cell division. One of the molecules thought to be critical for the transmission and amplification of mitogenic signals from the cell surface to the nucleus is the proto-oncogene product Raf-1. Raf-1 is a serine-threonine kinase that is itself phosphorylated in response to mitogenic stimulation. The phosphorylation state of Raf-1 appears to modulate its kinase activity. Experiments linking Raf-1 to other characterized components of the signal transduction machinery are reviewed here.