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

Basic fibroblast growth factor (bFGF) is a major factor contributing to human melanoma cell growth. bFGF is produced constitutively by cells from each stage of the disease, but not by normal melanocytes, although the latter cells are dependent on the factor for growth in vitro. Two lines of evidence suggest that bFGF functions in an autocrine manner in melanoma: (1) inhibition of bFGF activity by bFGF-specific antibodies or antisense sequences suppresses melanoma cell growth in vitro; and (2) retrovirus-mediated transfer of a bFGF cDNA into normal murine melanocytes renders the recipient cell bFGF-independent. Constitutive production of bFGF is not by itself sufficient for the establishment of the transformed phenotype, however, since bFGF-expressing melanocytes are neither immortalized nor tumorigenic in nude mice.

It has become increasingly apparent that growth factor receptors can function as oncogenic proteins and play causal roles in cell transformation. A prime example is the epidermal growth factor receptor (EGFR), which belongs to the ligand-activated tyrosine kinase receptor family and is overexpressed in certain human tumors. The transforming gene of avian erythroblastosis virus, v-erbB, encodes a truncated form of the EGFR whose kinase domain is constitutively activated by deletion of the ligand binding domain. Recent comparative studies of the v-erbB gene in different viral isolates have revealed that subtle sequence changes (point mutations, small deletions) can alter both the pathogenic spectrum of the virus and the range of cell types susceptible to transformation in vitro. Therefore, the possibility exists that similar, as-yet-unidentified, mutations may exist in the EGFR gene; if so, the EGFR may be an oncogenic factor in tumors other than those with which it has been associated to date.

The stress response is ubiquitous among all organisms of the bacterial, plant, and animal kingdoms. A prominent feature of this response is the synthesis of a discrete set of proteins, known as heat shock proteins, that have been shown to be essential in a plethora of protein biosynthetic and processing reactions, including protein folding and oligomerization, translocation, and secretion. During heat shock and other forms of physiological stress, heat shock proteins act as intracellular sentinels to recognize malfolded proteins. The heat shock response is tightly regulated and encompasses selective transcriptional and translational mechanisms that control the preferential synthesis of stress proteins during physiological stress. Deregulation of stress gene expression is associated with various human diseases. It is likely that the balance of interactions between damaged protein molecules and stress proteins has profound effects that impinge on normal cell growth and differentiation.

The "conventional" polyphosphoinositide pathway is important for the transmission and amplification of signals across the cell membrane. Ligand-induced activation of phospholipase C results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate to produce the well-characterized second messengers, inositol 1,4,5-trisphosphate and diacylglycerol. Recently, three novel polyphosphoinositides have been implicated as important signaling molecules for cell proliferation and activation. These lipids are phosphorylated in the D-3 position of the inositol ring and appear to represent branch points from the conventional polyphosphoinositide pathway.

Reduced expression and/or somatic allelic deletion of nm23 is associated with high metastatic potential in several types of rodent tumors and human breast and colorectal carcinomas. Transfection of murine nm23-1 cDNA into highly metastatic murine K-1735 TK melanoma cells results in a reduced incidence of primary tumor formation, significant reduction in tumor metastatic potential, and altered responsiveness to the cytokine, transforming growth factor beta. Here we discuss emerging concepts concerning nm23, such as its varied pattern of alteration/expression in tumor metastasis, its effect on tumorigenesis, and its possible biochemical functions.