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Journal of the National Cancer Institute, Vol. 98, No. 12, June 21, 2006 A tumor suppressor gene is generally defi ned as a gene whose loss of function promotes the replication of a transformed cell. Because the loss of function yields a malignant phenotype, and in most cases deletion or inactivation of both alleles is required ( 1 ) , most tumor suppressor genes have been identifi ed through linkage analyses in cancer families or through genome-wide analyses of loss of heterozygosity (LOH) that is frequent in tumors of a specifi c type. Many genes whose products infl uence cell growth in vitro fail this test, which makes identifying a new tumor suppressor gene perhaps one of the most daunting tasks in molecular biology. Solid in vitro evidence and supporting clinical data are required before a candidate gene can be defi ned as a tumor suppressor. Tsai et al. ( 2 ) present a comprehensive study that strongly supports the identifi cation of a heat shock protein family member as a new tumor suppressor gene. Using microarray analyses to compare invasive and non invasive non – small-cell lung cancers (NSCLCs) ( 3 ) , they identifi ed DNAJB4, the DnaJ-like heat shock protein (HLJ1), as a putative tumor suppressor gene that fulfi ls crucial criteria: reintroduction of HLJ1 expression inhibits lung cancer cell proliferation and anchorage-independent growth in vitro and xenograft tumorigenesis in vivo. Furthermore, they observed reduced expression and LOH of HLJ1 in most of the human NSCLC samples tested. Tumor suppressor genes for NSCLC are eagerly sought for both our understanding of lung cancer biology and the need of a prognostic marker. The extensive basic and translational studies of another suppressor, fragile histidine triad (FHIT) ( 4 ) , testify to the importance of these markers in the fi eld. Despite the fact that metastasis remains the critical problem for lung cancer patients and that angiogenesis is closely linked with outcome in NSCLC ( 5 ) , the potential anti-invasive and anti-angiogenic properties of FHIT have yet to be thoroughly investigated. Tsai et al. report that higher HLJ1 expression levels are associated with better patient outcome, in terms of reduced recurrence and longer overall survival, which suggests a less aggressive and less metastatic phenotype. The authors found that HLJ1 acts via the STAT/P21 WAF1 pathway to inhibit passage through S phase, and it does so in a p53 and interferon independent manner ( 2 ) . Many cellular pathways related to cell growth, DNA integrity, and apoptosis converge on p53 ( 6 ) , a tumor suppressor that is mutated in most human tumors. Important questions remain: Do p53 and HLJ1 mutations occur concomitantly or in a mutually exclusive pattern? Does HLJ1 loss or mutation contribute to the malignant phenotype of cells bearing p53 mutations in an additive or a synergistic way? Is its tumor-suppressive power quantitatively comparable to that exerted by p53, or is it just another cell cycle control factor, important for only a few cancer types? Other suppressor genes for NSCLCs, such as FHIT ( 4 ) and tumor suppressor of lung cancer (TSLC) 1 ( 7 ) appear to be preferentially associated with lung cancers in smokers, a fact that EDITORIALS

A New Tumor Suppressor Gene: Invasion, Metastasis, and Angiogenesis as Potential Key Targets