Anti-ROR2 monoclonal antibody, clone Ou3646-3946

Receptor tyrosine kinases (RTKs) play a role in various processes, including cell growth, differentiation, apoptosis and carcinogenesis. RTKs are activated in various types of cancers, including breast, stomach, colon, pancreas and liver cancer and hepatocellular carcinoma (HCC). In the present study, protein array technology was used to analyze the expression status of various RTKs activated in HCC. The expression of activated RTKs was examined in the HCC cell lines, Alex, HuH7, Li-7, Hep3B, HLE and HLF; in the human normal hepatocyte cell line, hNHeps; and in human HCC and adjacent non-cancerous tissues. Of the 42 different phospho-RTKs, 15 (ErbB2, ErbB3, ErbB4, FGER2 alpha, FGER3, insulin R, Mer, PDGFR beta, c-Ret, ROR2, Tie, TrkA, VEGFR3, EphA1 and EphA4) were activated in some of the cancer cell lines studied. Among these, only ErbB2 was activated in all the HCC cell lines examined. Also, in vitro experiments were performed in subcutaneous HCC-bearing athymic nude mice to determine the therapeutic effects of inhibiting ErbB2 activation using the ErbB2-targeting drug trastuzumab. The results revealed that trastuzumab markedly suppressed the growth of HCC. These data suggest that ErbB2 is activated in HCC and that trastuzumab may play a role in the treatment of this disease. In addition, the use of protein array technology is proposed as a tool for detecting the expression of activated RTKs and identifying an effective RTK-based therapy.

Ben-Shachar S, Khajavi M, Withers MA, Shaw CA, van Bokhoven H, Brunner HG, Lupski JR. Dominant versus recessive traits conveyed by allelic mutations - to what extent is nonsense-mediated decay involved?Clin Genet 2009: 75: 394-400. (C) Blackwell Munksgaard, 2009 Mutations in ROR2, encoding a receptor tyrosine kinase, can cause autosomal recessive Robinow syndrome (RRS), a severe skeletal dysplasia with limb shortening, brachydactyly, and a dysmorphic facial appearance. Other mutations in ROR2 result in the autosomal dominant disease, brachydactyly type B (BDB1). No functional mechanisms have been delineated to effectively explain the association between mutations and different modes of inheritance causing different phenotypes. BDB1-causing mutations in ROR2 result from heterozygous premature termination codons (PTCs) in downstream exons and the conveyed phenotype segregates as an autosomal dominant trait, whereas heterozygous missense mutations and PTCs in upstream exons result in carrier status for RRS. Given that the distribution of PTC mutations revealed a correlation between the phenotype and the mode of inheritance conveyed, we investigated the potential role for the nonsense-mediated decay (NMD) pathway in the abrogation of possible aberrant effects of selected mutant alleles. Our experiments show that triggering or escaping NMD may cause different phenotypes with a distinct mode of inheritance. We generalize these findings to other disease-associated genes by examining PTC mutation distribution correlation with conveyed phenotype and inheritance patterns. Indeed, NMD may explain distinct phenotypes and different inheritance patterns conveyed by allelic truncating mutations enabling better genotype-phenotype correlations in several other disorders.