Toshio Harada

Integrin α2 Mediates Selective Metastasis to the Liver

Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad array of cell membrane molecules on a liver-metastasizing subline of B16 melanoma versus the parental B16-F0 revealed unique up-regulation of integrin alpha2. The direct role of integrin alpha2 in hepatic metastasis was shown by comparison of high versus low-expressing populations, antibody blockade, and ectopic expression. Integrin alpha2-mediated binding to collagen type IV (highly exposed in the liver sinusoids) and collagen type IV-dependent activation of focal adhesion kinase are both known to be important in the metastatic process. Analysis of primary colorectal cancers as well as coexisting liver and lung metastases from individual patients suggests that integrin alpha2 expression contributes to liver metastasis in human colorectal cancer. These findings define integrin alpha2 as a molecule conferring selective potential for formation of hepatic metastasis, as well as a possible target to prevent their formation.

Expression of tropomyosin alpha 4 chain is increased in esophageal squamous cell carcinoma as evidenced by proteomic profiling by two-dimensional electrophoresis and liquid chromatography-mass spectrometry/mass spectrometry

To identify proteins associated with esophageal carcinogenesis, we performed protein profiling of 16 esophageal squamous cell carcinomas (ESCCs) and paired noncancerous tissues by 2‐DE and MS/MS. In cancerous tissues, three spots showed significant up‐regulation in the amount of protein, while eight spots were significantly down‐regulated. The identities of the spots were determined by PMF with LC‐MS/MS and were confirmed by immunoblotting. The up‐regulated proteins were tropomyosin alpha 4 chain, transgelin, and pyruvate kinase. The down‐regulated proteins were serum albumin precursor, isoforms of annexin A1, tropomyosin beta chain, 14‐3‐3 protein sigma, and isoforms of serotransferrin precursor. In all 16 cases, up‐regulation of the tropomyosin alpha 4 chain was confirmed by immunoblotting. Localization of the tropomyosin alpha 4 chain in ESCC cells and adjacent fibroblasts was confirmed by immunohistochemistry.

Studies on fused pyrimidine derivatives. Part 14. Formation and transformation of [4 + 2] cycloadducts, cyclohepta[g]quinazoline derivatives, by the reaction of 5-(arylaminomethylene)-1,3-dimethyl-6-methyleneperhydropyrimidine-2,4-diones with tropone

The reaction of 5-(arylaminomethylene)-1,3-dimethyl-6-methyleneperhydropyrimidine-2,4-diones 3 with tropone 4 gave two diastereoisomeric [4 + 2] cycloadducts, cyclohepta[g]quinazolines 5 and 6. These products correspond to endo- and exo-approach of enamine 3 to the 2,3-double bond of tropone 4, respectively. The chemical behaviour of the endo- and exo- adducts will be discussed. The X-ray structures of 5-(4-bromoanilino)-1,3-dimethyl-2,3,4,r-5,c-5a,10,c-10a,11-octahydro-1H-cyclohepta[g]quinazoline-2,4,10-trione, 5-(4-bromoanilino)-1,3-dimethyl-2,3,4,r-5,t-5a,10,t-10a,11-octahydro-1H-cyclohepta[g]quinazoline-2,4,10-trione and 12,14-Dimethyl-r-6b,9,10,c-10a,11,12,13,14,15,c-15b,c-15c,16-dodecahydrobenzo[c]-cyclohepta[kl]pyrimido[5,4-h]acridine-10,13,15-trione are described.