Thymocyte and thymic epithelial cell (TEC) development are interdependent processes. Although lineage relationships among progressively maturing thymocyte subsets have been characterized, the developmental relationships among TEC subsets are obscure. Because epithelial cells express distinct keratin (K) species as a function of differentiation stage and proliferative status, we used K expression patterns to identify mouse TEC subsets and determine their lineage relationships. CD25ϩ pre-T cells that productively rearrange the TCR␤ locus and express pre-TCR͞CD3 complexes proliferate and differentiate to the CD4 ϩ CD8 ϩ double-positive (DP) stage. The DN to DP transition is accompanied by loss of CD25 expression, prohibition of TCR␤ locus rearrangements, and induction of TCR␣ locus rearrangements. Signaling through the ␣␤TCR͞CD3 complexes on DP thymocytes mediates the positive and negative selection processes that shape the T-cell repertoire. DP thymocytes that are positively selected by self-peptide͞major histocompatibility complex molecules presented on cortical epithelial cells terminate CD8 or CD4 expression and migrate to the thymic medulla.Thymic epithelial cells (TECs) are not only involved in the selection of DP cells, but also promote differentiation of early DN thymocyte precursors. Nude mice that are unable to generate a normal thymic epithelial compartment because of an inactivating whn gene mutation have a primitive thymic anlage devoid of T cells (3). Furthermore, recent studies have shown that the maturation of DN precursors in thymic organ culture requires the presence of major histocompatibility complex class II ϩ TECs (4-6). Although TECs are known to play a critical role in T-cell maturation, the factors that govern TEC development are incompletely understood, particularly in comparison to the well-characterized T-cell developmental process. Nevertheless, it is clear that the establishment of normal thymic architecture and thus, TEC differentiation, depends on thymocyte͞TEC interactions (7,8). This interdependence is apparent in mice that express a human CD3 (hCD3) transgene, which prevents T-cell maturation beyond the primitive CD44 ϩ CD25 Ϫ

Testing of prostate cancer biopsy specimens from metastatic sites for p53 protein accumulation and gene mutation may provide useful prognostic information and could influence the recommended course of treatment.

Epidemiological and dietary studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colon cancer, possibly through a mechanism involving inhibition of cyclooxygenase (COX)-2, which is overexpressed in premalignant adenomatous polyps and colon cancer. Because ultraviolet light (UV) can induce COX-2 and nonspecific NSAIDs can decrease UV-induced skin cancer, we evaluated the ability of two compounds, celecoxib (a specific COX-2 inhibitor) and indomethacin (a nonspecific NSAID), to block UV-induced skin tumor development in SKH:HR-1-hrBr hairless mice. Mice fed 150 or 500 ppm celecoxib showed a dose-dependent reduction (60% and 89%, respectively) in tumor yield. Indomethacin (4ppm) reduced tumor yield by 78%. Although both acute and chronic UV exposure increased cell proliferation and edema, neither compound reduced these parameters. In contrast, UV-induced prostaglandin synthesis in the epidermis was effectively blocked by both compounds. UV-induced increases in COX-2 expression in skin were also not altered in any of the treatment groups. Similarly, tumors that constitutively express high levels of COX-2 displayed no reduction by treatment with celecoxib or indomethacin. The dramatic protective effects of celecoxib suggests that specific COX-2 inhibitors may offer a way to safely reduce the risk of skin cancer in humans.

Cyclin D1 is part of a cell cycle control node consistently deregulated in most human cancers. However, studies with cyclin D1-null mice indicate that it is dispensable for normal mouse development as well as cell growth in culture. Here, we provide evidence that ras-mediated tumorigenesis depends on signaling pathways that act preferentially through cyclin D1. Cyclin D1 expression and the activity of its associated kinase are up-regulated in keratinocytes in response to oncogenic ras. Furthermore, cyclin D1 deficiency results in up to an 80% decrease in the development of squamous tumors generated through either grafting of retroviral ras-transduced keratinocytes, phorbol ester treatment of ras transgenic mice, or twostage carcinogenesis.