APOPTOSIS-DRIVEN FIBROSIS IN THE LIVER—IT'S NOT JUST CYTOKINES ANYMORE!
Hepatic injury often leads to liver fibrosis, which if extensive can result in cirrhosis replete with the clinical complications of portal hypertension, its sequelae, and chronic progressive liver failure. The hepatic stellate cell (the Ito cell) has been implicated as a major contributor in the development of hepatic fibrosis and cirrhosis. Its transition into a "myofibroblast"-like cell with a robust collagen synthetic capacity is thought to be a cytokine-mediated process. Indeed, selected cytokines including TGF-
have been implicated in this process as well as in the maintenance of this activated phenotype. In this issue, Canbay et al examine the potential role of hepatocyte apoptosis (another prominent feature of hepatic injury) in directly and indirectly initiating and maintaining the activated stellate cell phenotype (Lab Invest 2003, 83: 655–664). Their findings using primary and immortalized human stellate cells demonstrate that stellate cells indeed engulf apoptotic bodies, which was found to be associated with increased TGF- and type I collagen induction, suggesting a direct link between hepatocyte apoptosis, stellate cell activation, and the development of hepatic fibrosis. These findings, coupled with the knowledge that apoptosis by macrophages (Kupffer cells) elicits increased cytokine expression, are consistent with the concept that continued hepatocyte apoptosis can function as a sustained stimulus for direct and indirect (cytokine-mediated) activation of hepatic stellate cells.
LMP1 PHENOTYPES
Nasopharyngeal carcinoma (NPC) is common in Southern China and is thought to involve infection by Epstein-Barr virus (EBV). The latent membrane protein 1 "LMP1" is one of a few EBV genes expressed in NPC. It attracted special attention because of its ability to transform fibroblasts, thanks to its activated growth factor receptor-like properties. In fibroblasts, and in human epithelial culture systems, de novo LMP1 expression has been linked to increased survival, proliferation, motility, and reduced differentiation. Despite extensive study, there is relatively little information on interactions of LMP1 with the target nasopharyngeal epithelium. A recent advance was the derivation of immortal NPC cell lines by infection of human nasal epithelium with viruses carrying papillomavirus or SV40 tumor antigens. In this issue, one of these cell lines is now analyzed after introduction of an LMP1 gene. Lo et al find that introduction of LMP1 induces a transformed phenotype, marked by increased proliferation and reduced serum requirements; down-regulation of E-cadherin and up-regulation of vimentin characteristic of epithelial/mesenchymal transition; anchorage-independent growth; and increased cell motility and invasiveness (Lab Invest 2003, 83: 697–710). A limited cDNA array transcriptional analysis suggests changes comparable to those observed in other LMP1-transformed systems and identified some potentially interesting changes in novel effector transcripts. This work establishes another advance in the development of homologous model culture systems for investigating the pathogenesis of EBV. Although much can be learned from studies of "generic" epithelial and mesenchymal systems, the use of homologous systems may ultimately yield more subtle insights. There are caveats in interpretation of the results of this work: the lurking SV40 transgene may contribute cryptically to the phenotype. Also, the parental NPC cell line NP69 has many karyotypic abnormalities and may have unique properties that interact with LMP1 in transformation. Eventually, the use of conditional immortalization systems may further refine the development of these important culture models for human cancer. Nonetheless, the new transcriptional targets identified should prove fertile ground in investigation of NPC.
AGE AND DISEASE
The ability to study transcriptional patterns in tissues enables scientists to ask questions about variation in gene expression related to the aging process. Early studies of aging indicate that some changes in expression pattern are common to all the organs studied, but there is also evidence that organ-specific variations can be observed. Senescence-associated changes seem to render organs more susceptible to disease, and men of advanced age are prone to develop hyperplasia of the prostate and prostate cancer. One may ask what changes can be observed in the prostate gland of animal models and do these changes provide insights into the mechanism of human prostate pathology. Inside this issue, Lau et al use cDNA arrays to identify differentially expressed genes in the ventral prostate of old (16 months) and young (3 months) Noble rats (Lab Invest 2003, 83: 743–758). Of the 78 genes found to be differentially expressed, 65 showed reduced expression with age, and 13 genes were over-expressed when compared with young rats. Not surprisingly, the genes that declined are involved in protein synthesis, the maintenance of protein fidelity, anabolism, growth inhibition, and energy metabolism. The genes that were found to be over-expressed in the aging rat were linked to cell survival, suggesting that prolonged cell longevity concomitant to a degraded metabolic machinery predisposes the prostate to cancer. It will be interesting to follow the leads provided by this study and see if the patterns seen in human prostatic tissue follow those uncovered in the rodent. The hypothesis that erosion of the metabolic protein machinery could represent an epigenetic mechanism that contributes to the pathogenesis of prostate cancer seems worth pursuing and may well contribute an element of "chance" in the otherwise deterministic play of genes and environment!
