Mikio Ni~hizawa,~ Hepatic stellate cells (HSCs) spontaneously transdifferentiate into myofibroblast (MFB) -phenotype on plastic dishes. This response recapitulates the features of activation in viva Transforming growth &tor P (TGF-P) plays a prominent role in stimulating liver fibrogenesis by MFBs. In quiescent HSCs, TGF-P signaling involves TGF-P type I receptor (TPRI)-mediated phosphorylation of serine residues within the conserved SSXS motif at the C-terminus of Smad2 and Smad3. The middle linker regions of Smad2 and Smad3 also are phosphorylated by mitogenactivated protein b a s e (MAPK). This study elucidates the change of Smad3-mediated signals during the transdifferentiation process. By using antibodies highly specific to the phosphorylated C-terminal region and the phosphorylated linker region of Smad3, we found that TGF-& dependent Smad3 phosphorylation at the C-terminal region decreased, but that the phosphorylation at the linker region increased in the process of transdifferentiation. TGF-P activated the p38 MAPK pathway, further leading to Smad3 phosphorylation at the linker region in the cultured MFBs, irrespective of Smad2. The phosphorylation promoted hetero-complex formation and nuclear translocation of Smad3 and Smad4. Once combined with TPRI-phosphorylated Smad2, the Smad3 and Smad4 complex bound to plasminogen activator inhibitor-type I promoter could enhance the transcription. In addition, Smad3 phosphorylation mediated by the activated TPRI was impaired severely in MFBs during chronic liver injury, whereas Smad3 phosphorylation at the linker region was remarkably induced by p38 MAPK pathway. In conclusion, p38 MAPK-dependent Smad3 phosphorylation promoted extracellular matrix production in MFBs both in vitro and in viva (HEPATOLOGY 2003 age as well as after their prolonged culture on plastic dishes.' This process involves changes in the cell morphology and gene expression and is characterized by the gradual loss in the retinoid content and the synthesis of a large amount of extracellular matrix (ECM) components.Transforming growth factor P (TGF-P) is an important mediator of ECM accumulation and is involved in a variety of physiologic and pathologic processes.2 In particular, the expression of TGF-/3 at high steady-state levels associated with the accelerated ECM accumulation in MFBs is a common finding in human chronic liver disease of different etiologies.3 Uncontrolled ECM accumulation mediated by TGF-P is thought to be essential for the development of liver fibrosis. However, the change of TGF-P signals during the transdifferentiation process of HSCs remains unclear.O n the other hand, recent studies over the past several years have elucidated how TGF-P initiates its response. TGF-/3 transduces the signal from its receptor to nucleus through Smads.4 The activated TGF-P type I receptor (TPRI) phosphorylates such receptor-regulated Smads 879

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The incidence of prostate cancer (PCa) displays widespread regional differences, probably owing to differences in dietary habits. Nutrients, including fat, protein, carbohydrates, vitamins (vitamin A, D, and E), and polyphenols, potentially affect PCa pathogenesis and progression, as previously reported using animal models; however, clinical studies have reported controversial results for almost all nutrients. The effects of these nutrients may be manifested through various mechanisms including inflammation, antioxidant effects, and the action of sex hormones. Dietary patterns including the Western and Prudent patterns also influence the risk of PCa. Recent studies reported that the gut microbiota contribute to tumorigenesis in some organs. Diet composition and lifestyle have a direct and profound effect on the gut bacteria. Human studies reported an increase in the abundance of specific gut bacteria in PCa patients. Although there are few studies concerning their relationship, diet and nutrition could influence PCa, and this could be mediated by gut microbiota. An intervention of dietary patterns could contribute to the prevention of PCa. An intervention targeting dietary patterns may thus help prevent PCa.

Reliable biomarkers for renal cell carcinoma (RCC) have yet to be determined. Circulating tumor DNA (ctDNA) is an emerging resource to detect and monitor molecular characteristics of various tumors. The present study aims to clarify the clinical utility of ctDNA for RCC. Fifty‐three patients histologically diagnosed with clear cell RCC were enrolled. Targeted sequencing was carried out using plasma cell‐free DNA (cfDNA) and tumor DNA. We applied droplet digital PCR (ddPCR) to validate detected mutations. cfDNA fragment size was also evaluated using a microfluidics‐based platform and sequencing. Proportion of cfDNA fragments was defined as the ratio of small (50‐166 bp) to large (167‐250 bp) cfDNA fragments. Association of mutant allele frequency of ctDNA with clinical course was analyzed. Prognostic potential was evaluated using log‐rank test. A total of 38 mutations across 16 (30%) patients were identified from cfDNA, including mutations in TP53 (n = 6) and VHL (n = 5), and median mutant allele frequency of ctDNA was 10%. We designed specific ddPCR probes for 11 mutations and detected the same mutations in both cfDNA and tumor DNA. Positive ctDNA was significantly associated with a higher proportion of cfDNA fragments (P = .033), indicating RCC patients with ctDNA had shorter fragment sizes of cfDNA. Interestingly, the changes of mutant allele frequency in ctDNA concurrently correlated with clinical course. Positive ctDNA and fragmentation of cfDNA were significantly associated with poor cancer‐specific survival (P < .001, P = .011). In conclusion, our study shows the clinical utility of ctDNA status and cfDNA fragment size as biomarkers for prognosis and disease monitoring in RCC.

The prevalence of obesity is increasing in the world, and obesity-induced disease, insulin-resistance, cardiovascular disease, and malignancies are becoming a problem. Epidemiological studies have shown that obesity is associated with advanced prostate cancer and that obese men with prostate cancer have a poorer prognosis. Obesity induces systemic inflammation via several mechanisms. High-fat diet-induced prostate cancer progresses via adipose-secretory cytokines or chemokines. Inflammatory cells play important roles in tumor progression. A high-fat diet or obesity changes the local profile of immune cells, such as myeloid-derived suppressor cells and macrophages, in prostate cancer. Tumor-associated neutrophils, B cells, and complements may promote prostate cancer in the background of obesity. Interventions to control systemic and/or local inflammation and changes in lifestyle may also be viable therapies for prostate cancer.

Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-specific Pten knockout mice as a prostate cancer model to investigate whether there is a gut microbiota–mediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer–bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including Rikenellaceae and Clostridiales, inhibited prostate cancer cell proliferation, and reduced prostate Igf1 expression and circulating insulin-like growth factor-1 (IGF1) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGF1 receptor, were suppressed by Abx administration. IGF1 directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1 in vitro. Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF1 levels. In humans, IGF1 was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment. Significance: These results suggest that intestinal bacteria, acting through short-chain fatty acids, regulate systemic and local prostate IGF1 in the host, which can promote proliferation of prostate cancer cells.

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SummaryMany colorectal cancer cells are resistant to the anti-proliferative effects of transforming growth factor-β (TGF-β). TGF-β also acts as paracrine factor from cancer cells on their mesenchymal cells. The aim of this study was to examine the expression of TGF-β and its receptors in human colorectal cancer tissue and determine any relationship with cancer growth. In situ hybridization and Northern blot hybridization detection of TGF-β 1 , type I and type II receptor mRNA and immunohistochemical staining of TGF-β 1 were performed using 11 human colorectal adenomas, 22 colorectal cancers and ten normal colorectal mucosas as control. TGF-β receptor mRNAs were expressed mainly by normal colorectal epithelial cells and adenoma. However, mRNAs for TGF-β receptors were only faintly, if at all, expressed in eight of 22 human colorectal cancers. In addition, intense signals of TGF-β 1 mRNA and the protein were detected in all colorectal cancers. TGF-β receptor mRNAs and TGF-β 1 protein were also distributed in fibroblasts and endothelial cells in the interstitium. Moreover, Smad 4 protein was translocated to nucleus in primarily cultured adenoma cells, but not in cancer cells after TGF-β stimulation. The escape of human colon cancer from TGF-β -mediated growth inhibition by down-regulation of TGF-β receptors as well as the effects of TGF-β on stroma formation and angiogenesis indicate a possible role for TGF-β in the progression of colon cancer in an intact host.Keywords: TGF-β; TGF-β receptor; Smad, colorectal cancer; colorectal adenoma 194British Journal of Cancer (1999) 80(1/2), 194-205 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received 30 receptors, and alterations in post-receptor pathways. Several reports indicate that elevated levels of TGF-β mRNA and protein in colorectal cancer are associated with cancer progression (Tsushima et al, 1996). If TGF-β is indeed an inhibitor for epithelial cells, how then do colorectal cancer cells manage to proliferate despite elevated TGF-β production by tumour cells? Concerning the mechanisms of resistance to the anti-proliferative effects of TGF-β in colorectal cancer, Markowitz et al (1995) identified a specific TGF-β RII mutation that is associated with defective DNA mismatch repair in colon cancer cells. However, numerous reports also indicate that transcriptional regulation makes an important contribution to determination of the expression level of TGF-β receptors (Birchenall-Roberts et al, 1995;Kim et al, 1997). Accordingly, to clarify the mechanisms of resistance to the antiproliferative effects of TGF-β in vivo, we estimated the transcriptional level of TGF-β receptors in colorectal cancer using in situ hybridization and Northern blot hybridization as the standard for those in normal colorectal epithelial cells.In addition, no studies of human colorectal tumour to date have compared in situ levels of TGF-β 1 with those of its receptors as a presumptive target gene, and with the presence of ligand protein.To ascertain if TGF-β from colorectal cancer act...