T ransforming growth factor (TGF)-β is a multifunctional cytokine that regulates a wide range of cellular responses, including cell proliferation, differentiation, adhesion, migration, and apoptosis.(1,2) It is a potent inhibitor of various types of cells, including most epithelial cells, whereas it stimulates deposition of extracellular matrix proteins and induction of epithelialto-mesenchymal transition (EMT). TGF-β thus plays two distinct and opposing roles in cancer progression. In early stages of carcinogenesis, it acts as a tumor suppressor by preventing cell proliferation, although in advanced stages of cancer, tumor cells often become refractory to TGF-β-mediated growth inhibition. TGF-β is often overexpressed in tumor cells, and induces migration, invasion, and EMT of tumor cells and facilitates immunosuppression, deposition of extracellular matrix proteins and angiogenesis. TβR-II is the primary ligand-binding receptor at the cell surface and contains constitutively active kinase. Upon ligand binding, the TβR-II kinase transphosphorylates TβR-I, and TβR-I then transduces intracellular signals through various proteins, of which Smad proteins are the major signaling transducers for TGF-β.(6,7) Activated TβR-I phosphorylates receptor-regulated Smads (R-Smads), i.e. Smad2 and Smad3, which interact with common-mediator Smad (Smad4) and translocate to the nucleus where they regulate transcription of various target genes. Smad7 is an inhibitory Smad that inhibits TGF-β signaling through interaction with activated TβR-I and other mechanisms.TGF-β signaling can be regulated by various molecules, including antisense oligonucleotides to certain TGF-β isoforms, monoclonal antibodies to TGF-βs, soluble forms of TβR-II, and small-molecule compounds that act on TGF-β receptor kinases. (8) Of these, TβR-I kinase is one potential target for blockade of TGF-β signaling pathway. Recently, several small-molecule compounds that bind to and inhibit TβR-I kinase activity have been generated and shown to potently inhibit TGF-β activity in vitro and in vivo.(8) Small-molecule inhibitors of TβR-I kinase are highly specific for TβR-I, although they also inhibit kinase activities of closely related molecules, that is, type I receptors for activin and nodal (activin-receptor like kinase-4; ALK-4 and ALK-7). (9) An in vivo experimental bone metastasis model has been established using an intracardiac injection of cancer cells, including MDA-MB-231 cells. (10,11) In this model, growth of cancer cells arrested in bone is easily observed as the progression of osteolysis on radiographs. This model is thus frequently used to explore the molecular interactions between the cancer cells and bone microenvironment. Several studies using this in vivo model suggested that TGF-β and its transcriptional targets, including parathyroid hormone-related protein (PTHrP) and interleukin-11 (IL-11), are the essential mediators of bone metastasis. (12,13) More recent studies have revealed that Smad signaling is essential for the development of bone metas...

To identify molecules to serve as diagnostic markers for renal cell carcinoma (RCC) and as targets for novel therapeutic drugs, we investigated genome-wide expression profiles of RCCs using a cDNA microarray. We subsequently confirmed that hypoxia-inducible protein-2 (HIG2) was expressed exclusively in RCCs and fetal kidney. Induction of HIG2 cDNA into COS7 cells led to secretion of the gene product into culture medium and resulted in enhancement of cell growth. Small interfering RNA effectively inhibited expression of HIG2 in human RCC cells that endogenously expressed high levels of the protein and significantly suppressed cell growth. Moreover, addition of polyclonal anti-HIG2 antibody into culture medium induced apoptosis in RCC-derived cell lines. By binding to an extracellular domain of frizzled homologue 10 (FZD10), HIG2 protein enhanced oncogenic Wnt signaling and its own transcription, suggesting that this product is likely to function as an autocrine growth factor. ELISA analysis of clinical samples identified secretion of HIG2 protein into the plasma of RCC patients even at an early stage of tumor development, whereas it was detected at significantly lower levels in healthy volunteers or patients with chronic glomerulonephritis. The combined evidence suggests that this molecule represents a promising candidate for development of molecular-targeting therapy and could serve as a prominent diagnostic tumor marker for patients with renal carcinomas. (Cancer Res 2005; 65(11): 4817-26)

Transforming growth factor-B (TGF-B) signaling facilitates tumor growth and metastasis in advanced cancer. In the present study, we identified differentially expressed in chondrocytes 1 (DEC1, also known as SHARP2 and Stra13) as a downstream target of TGF-B signaling, which promotes the survival of breast cancer cells. In the mouse mammary carcinoma cell lines JygMC(A) and 4T1, the TGF-B type I receptor kinase inhibitors A-44-03 and SB431542 induced apoptosis of cells under serum-free conditions. Oligonucleotide microarray and real-time reverse transcription-PCR analyses revealed that TGF-B induced DEC1 in these cells, and the increase of DEC1 was suppressed by the TGF-B type I receptor kinase inhibitors as well as by expression of dominant-negative TGF-B type II receptor. Overexpression of DEC1 prevented the apoptosis of JygMC(A) cells induced by A-44-03, and knockdown of endogenous DEC1 abrogated TGF-B-promoted cell survival. Moreover, a dominant-negative mutant of DEC1 prevented lung and liver metastasis of JygMC(A) cells in vivo. Our observations thus provide new insights into the molecular mechanisms governing TGF-Bmediated cell survival and metastasis of cancer. [Cancer Res 2007;67(20):9694-703]

The therapeutic techniques of carbon ion therapy have been established for patients with prostate cancer. Carbon ion therapy may exert excellent effect to the tissues of prostate cancer.

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