The promise of biomarkers in cancer screening and detection.

Despite the recent decline in the incidence of cancer, long-term mortality rates remain unchanged. One of the most important factors in the survival of cancer is detection at an early stage. Clinical assays that detect the early events of cancer offer an opportunity to intervene and prevent cancer progression. Biomarkers are important molecular signatures of the phenotype of a cell that aid in early cancer detection and risk assessment. Although new information and technologies are clearly important for new biomarker discovery, we face major hurdles in translating new findings into clinical application. Here, we discuss examples of recent advances and limitations in cancer biomarker identification and validation, and the implications for cancer prevention.

BCR engagement induces Fas resistance in primary B cells in the absence of functional Bruton's tyrosine kinase.

B cell susceptibility to Fas-mediated apoptosis is regulated in a receptor-specific fashion. CD40 engagement produces marked sensitivity to Fas killing, whereas surface Ig (sIg) engagement blocks Fas signaling for cell death in otherwise sensitive, CD40-stimulated B cell targets, and thus, induces a state of Fas resistance. The signaling mediator, Bruton's tyrosine kinase (Btk), is required for certain sIg-triggered responses, and Btk is reported to directly bind Fas and block Fas-mediated apoptosis. For these reasons, the role of Btk as a mediator of sIg-induced Fas resistance was examined. Dysfunction of Btk through mutation, and absence of Btk through deletion did not interfere with induction of Fas resistance by anti-Ig. This may be due, at least in part, to induction of Btk-dependent Bcl-2 family members by anti-Ig after CD40 ligand treatment. However, the susceptibility to Fas-mediated apoptosis of B cell targets stimulated by CD40 ligand alone was increased in the absence of Btk. These results indicate that Fas resistance produced by sIg triggering does not require Btk, but suggests that in certain situations Btk modulates B cell susceptibility to Fas killing.

B cell activation leads to upregulated expression of the murine Sik-similar protein gene.

B cells stimulated by the combination of CD40L plus anti-Ig were screened for upregulated gene expression in an unbiased fashion through differential display. An inducible transcript was obtained that corresponds to a sequence previously isolated from pre-B cells and termed murine Sik-similar protein (mSSP). The mSSP gene is predominantly expressed in lymphoid tissues, including spleen and thymus, as well as testis, with lesser amounts in kidney and ovary. Among lymphocyte cell lines, mSSP expression varies widely. The mSSP protein is localized to the nucleus in NIH3T3 cells, and its expression in BAL-17 B cells varies with cell cycle progression. Expression of mSSP increased significantly within the first hours of B cell treatment with either CD40L, anti-IgM, or phorbol myristate acetate (PMA) with or without ionomycin. The predicted amino acid sequence of mSSP bears some homology to proteins involved in ribosomal RNA synthesis and processing. mSSP is a previously identified pre-B cell gene now shown for the first time to be an activation-responsive transcript in mature, primary B cells.