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

Tumor metastasis is associated with an increase in the plasticity of malignant cells, a phenomenon that is characterized by changes in cell morphology and a decrease in intercellular cohesiveness. The plasticity of cells is correlated with their motility. Therefore, factors that enhance plasticity promote the migration of malignant cells from a primary tumor. Several cytokines that induce the dissociation and dispersal of malignant cells have now been described. By inhibiting the activity of motogenic cytokines, it may be possible to design effective strategies for the treatment of patients with metastatic cancer.

Cells acquire cholesterol via de novo synthesis and receptor-mediated uptake of low-density lipoprotein (LDL), the major cholesterol-carrying lipoprotein in blood. Human leukemic cells and certain tumor tissues display elevated receptor-mediated uptake of LDL as compared with the corresponding normal cells or tissues. LDL has therefore been proposed as a potential carrier for chemotherapeutic agents. Various methods have been employed to incorporate antineoplastic lipophilic drugs into LDL, and the resultant drug-LDL complexes have been shown to be cytotoxic toward tumor cells in vitro. Initial experiments with tumor-bearing animals suggest that LDL may be a promising carrier for drugs in the treatment of malignant diseases.

Hydrolysis of the neurotransmitter acetylcholine by acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) is the rate-limiting step in the termination of cholinergic signaling at neuromuscular junctions. A growing body of evidence suggests that these enzymes also play a role in tumorigenesis. The ACHE and BCHE genes are amplified, mutated, and/or aberrantly expressed in a variety of human tumor types. These changes could be the result of chromosome breakage, since there is an unusually high frequency of chromosomal abnormalities near the map positions of these genes (3q26-ter and 11p-ter, respectively) in such tumors, particularly hemopoietic malignancies. Both ACHE and BCHE contain the consensus peptide motif S/T-P-X-Z, which is found in many substrates of cdc2-related protein kinases. Here we consider the intriguing possibility that phosphorylation by cdc2-related kinases may be the molecular mechanism linking cholinesterases with tumor cell proliferation. We also discuss the notion that inhibition of these enzymes by commonly used organophosphorous poisons may be tumorigenic in humans.

Essentially all tumors express aberrantly glycosylated glycosphingolipids and glycoproteins, more commonly known as "tumor-associated carbohydrate antigens." In this article I propose two new forms of cancer therapy, anti-adhesion therapy and ortho-signaling therapy, which exploit these tumor-associated carbohydrates in distinct ways. The aim of anti-adhesion therapy is to disrupt the requisite carbohydrate-initiated interactions that occur between tumor cells and other cell types (e.g., endothelial cells, platelets) as tumors progress and metastasize. Candidate anti-adhesion agents include purified carbohydrates or glycosphingolipids representing H, Ley, sialosyl-Lex (or -Lea) GM3, or LacCer antigens, and monoclonal antibodies directed to these structures. The aim of ortho-signaling therapy is to disrupt mitogenic signaling pathways in tumor cells that are regulated by glycosphingolipids and/or their derivatives, including pathways involving receptor protein-kinases and protein kinase C. Candidate ortho-signaling agents are the glycosphingolipid regulator PDMP (1-phenyl-2-[decanoylamino]-3-morpholino-1-propanol) and the protein kinase C inhibitor DMS (N,N-dimethylsphingosine), both of which show antitumor activity in vitro and in animal studies.

Mouse strains carrying mutations at the Dominant White Spotting (W) locus or the Steel (Sl) locus are anemic and display defects in pigmentation and gametogenesis. In W mutants the anemia is due to a deficiency of hemopoietic stem cells and, in Sl mutants, to a deficiency of supporting stromal cells in the bone marrow. The W locus encodes the c-kit proto-oncogene product, a cell surface receptor with protein-tyrosine kinase activity, and the Sl locus encodes its ligand, a hemopoietic cytokine known variously as Steel factor (SLF), mast cell growth factor, stem cell factor, and Kit ligand. SLF can synergize with a number of other cytokines to stimulate growth of hemopoietic progenitors in vitro and stimulates blood cell production in vivo in animals. Here we review the biological activities of SLF, with particular emphasis on its effects on hemopoietic stem and progenitor cells. We also discuss present knowledge of the molecules involved in SLF-triggered signal transduction, and speculate on potential therapeutic applications for SLF in human disease.

Small-cell lung cancer (SCLC), the most common neuroendocrine tumor in humans, provides an excellent model system for analyzing the role of growth factors in lung cancer. SCLCs secrete a wide range of peptide hormones, including some that stimulate tumor cell growth, such as gastrin-releasing peptide and insulin-like growth factor I. Many of these peptides are synthesized as prohormones that acquire biological activity only after specific post-translational modifications. Here, we review our current understanding of the biological role of neuroendocrine peptides in lung carcinogenesis and consider how a mechanistic knowledge of one particular modification, carboxy-terminal alpha-amidation, may permit identification of novel growth factors for lung cancer cells. We also describe potential applications of this knowledge as a basis for prevention-oriented approaches to the disease.

Activation of T cells is associated with a dramatic increase in expression of the interleukin-2 receptor. In addition to the intact receptor found at the cell surface, activated T cells produce a truncated form of the receptor (sIL-2R) that is secreted as a soluble molecule. Patients with neoplastic disease or diseases involving immune activation exhibit markedly elevated serum levels of sIL-2R. Although the functional significance of sIL-2R is unknown, the ability to measure this parameter rapidly and accurately in serum samples makes it a potentially useful index for monitoring disease activity. Recent studies indicate that a rise in serum levels of sIL-2R in apparently healthy individuals could be an important early signal of neoplastic, autoimmune, or inflammatory disease. Moreover, subsequent to diagnosis, serum levels of sIL-2R appear to be a reliable indicator of tumor burden and therapeutic response for many patients with leukemia and lymphoma, an indicator of metastasis for patients with solid tumors, and an indicator of exacerbation and clinical response in patients with diseases associated with immune activation.

The JE gene was one of the first growth-factor-inducible early-response genes to be identified. Sequence and expression analysis have revealed that JE encodes the monocyte-specific cytokine MCP-1 (also known as MCAF, TDCF, and SMC-CF). JE/MCP-1 specifically attracts monocytes in vitro and in vivo, but has no detectable effects on neutrophils or lymphocytes. In addition, JE/MCP-1 can suppress tumor formation in animal models by attracting and activating monocytes. These discoveries have drawn together the investigations of those who study the molecular basis of cell proliferation and those who work on the molecular basis of the inflammatory response.