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

Mutated ras genes can acquire a transforming potential and are frequently detected in human tumors. The mammalian ras gene family includes at least 35 distinct members that can be divided into three main groups on the basis of their sequence similarity to ras, rho, or rab genes. All these genes encode small GTP-binding proteins. Rho proteins are implicated in actin organization and control of cell shape, probably by interacting with the cytoskeleton and intracellular membranes. Rab proteins are involved in vesicular traffic, and appear to control the translocation of vesicles from donor to acceptor membranes. The precise function of ras proteins is unknown, although the prevailing view is that they act as transducers of mitogenic signals. We propose that ras proteins, by analogy with rho and rab, are involved in the lateral segregation of multi-protein complexes at the plasma membrane, and we suggest how this process may be important for mitogenic signal transduction.

The ability to grow cells in monolayer culture has afforded investigators the opportunity to study many aspects of cancer cell biology under carefully controlled conditions. Nonetheless, an important factor that has often been overlooked is that cells in this configuration undergo a loss of structural integrity that may significantly alter their functional properties. Three-dimensional histoculture represents a useful alternative approach to monolayer culture because it preserves the native architecture of cells while still allowing ease of experimental manipulation. This review discusses the origins of three-dimensional cultures, the potential application of these cultures to assays of tumor cell metastasis and drug sensitivity, and the evidence from gene expression studies that these cultures may be more realistic tumor models than cell monolayers.

Delivery of monoclonal antibodies to solid tumors is a vexing problem that must be solved if these antibodies are to realize their promise in therapy. Such success as has been achieved with monoclonal antibodies is attributable to the local hyperpermeability of the tumor vasculature, a property that favors antibody extravasation at tumor sites and that is mediated by a tumor-secreted vascular permeability factor. However, leaky tumor blood vessels are generally some distance removed from target tumor cells, separated by stroma and by other tumor cells that together represent significant barriers to penetration by extravasated monoclonal antibodies. For this reason, alternative approaches may be attractive. These include the use of antibody-linked cytotoxins, which are able to kill tumor cells without immediate contact, and direction of antibodies against nontumor cell targets, for example, antigens unique to the tumor vascular endothelium or to tumor stroma.

The CCPC 90 conference and workshop included presentations by basic scientists describing the key in vitro and in vivo model systems used to study epithelial carcinogenesis and its associated biochemical and molecular alterations. A major conference theme was the identification of markers identifying specific carcinogenic stages. Current work focuses on defining the biology of preneoplasia, the critical specific molecular events in multistep carcinogenesis, and the dynamic interplay between viral, behavioral, dietary, and genetic factors in human carcinogenesis. Studies of molecular epidemiology and genetic susceptibility are identifying new risk groups and contributing to preventive strategies. Another major theme of the conference was the concept of field carcinogenesis and the study of carcinogen-exposed tissue "at risk" for the development of cancer. A specific example discussed by several investigators was the issue of SPT development in head and neck and lung cancers. Novel studies of biologic markers for use in early detection and as intermediate end points were described. The latter application, if validated in human trials, may allow short-term screening of chemopreventive agents and determinations of optimal doses/schedules for phase III chemoprevention trials. These biomarker trials may serve as a bridge between preclinical work and full-scale randomized trials. The status of the major phase III clinical trials was presented. Major problems in chemoprevention trials include (1) selection of agents, doses, and schedules, (2) lack of pharmacologic and pharma quality control, (5) adherence (drop-out and drop-in), and (6) trial-specific feasibility/recruitment, issues.

A complete understanding of the organization of the human hematopoietic stem cell hierarchy and of the molecular events regulating the stem cell developmental program has been hampered by the absence of suitable in vivo stem cell assays. Perturbations in the normal stem cell program that lead to neoplastic growth are also difficult to study because leukemic cells do not grow readily in culture. Recent advances in the transplantation of human cells into immune-deficient mice provide an unprecedented opportunity to study human hematopoiesis--both normal and abnormal--in the context of a small animal model. Here I review several of these new animal models and the basic concepts of murine and human hematopoiesis which led to their development.

Most types of human tumors display a consistent set of genetic alterations that are thought to play a role in tumor development and progression. In the case of gastric carcinomas, consistent genetic changes have been difficult to identify because (1) the tumor DNA samples are often heavily contaminated with DNA from normal stromal cells and (2) the tumors are heterogeneous in origin. However, with the recent application of more refined molecular genetic techniques, it has become clear that gastric carcinomas display some of the same genetic alterations observed in other common carcinomas. These changes include point mutation of the ras oncogene and the p53 tumor suppressor gene, gene amplification, and chromosomal loss of heterozygosity.