Expression of STAT3 in Prostate Cancer Metastases

STAT3 and its upstream activator IL6R have been implicated in the progression of prostate cancer and are possible future therapeutic targets. We analyzed 223 metastatic samples from rapid autopsies of 71 patients who had died of castration-resistant prostate cancer (CRPC) to study protein and gene expression of pSTAT3 and IL6R. Immunohistochemical analysis revealed that 95% of metastases were positive for pSTAT3 and IL6R, with varying expression levels. Bone metastases showed significantly higher expression of both pSTAT3 and IL6R in comparison to lymph node and visceral metastases. STAT3 mRNA levels were significantly higher in bone than in lymph node and visceral metastases, whereas no significant difference in IL6R mRNA expression was observed. Our study strongly supports the suggested view of targeting STAT3 as a therapeutic option in patients with metastatic CRPC. Patient summary We studied the levels of two proteins (pSTAT3 and IL6R) in metastases from patients who died from castration-resistant prostate cancer. We found high levels of pSTAT3and IL6R in bone metastases, suggesting that these proteins could be used as targets for new anticancer drugs

Carbonate Ions and Gastric Cancer

Nearly one million new cases of gastric cancer are diagnosed annually throughout the world. Even though the incidence has fallen dramatically in recent decades, this disease is still the second leading cause of cancer death in a global perspective. The geographic distribution of gastric cancer varies markedly, with the highest rates in Asian countries such as Japan, Korea, and China. This variation is presumably associated with modifiable risk factors, primarily H. pylori infection and diet, which have dominated the debate on this topic for more than a decade. The incidence of spontaneous gastric cancer is extremely low in rats, which has led to testing of different experimental models in attempts to generate gastric tumors in these animals. In the first study underlying this thesis, rats were subjected to gastric resection to generate duodenogastric reflux (DGR) and subsequent development of gastric adenocarcinomas. The effects of various food supplements on the incidence of cancer were studied using a total of 256 male Wistar rats. Surprisingly, in the first set of experiments in the second study, ingestion of food supplemented with calcium carbonate more than tripled the incidence of carcinomas (61%) compared to controls (17%). In a second set of experiments, calcium ions were switched to sodium ions, which revealed that carbonate ions caused the remarkable increase in cancer in the rats given an altered diet (54%, compared to 12% for controls). Both experimental and clinical studies have shown that DGR is associated with the development of gastric cancer. It has also been found that pancreaticoduodenal juice is responsible for the neoplastic formation, and that such fluid is especially rich in carbonate ions. The final study examined non-transformed mucosa in a rat model of gastric cancer to determine expression of COX-2 and ODC as markers of tumor promotion and to measure production of Ki67 as an indication of cell proliferation. This was done to assess the effect of carbonate ions on gastric tumorigenesis. The results indicated that the gastric resection per se increased COX-2 expression and significantly augmented cell proliferation. Dietary supplementation of carbonate ions did not further enhance the levels of COX-2. However, in the resected animals, carbonate-supplemented food led to elevated expression of ODC and a further increase in cell proliferation in the non-transformed mucosa. In conclusion, an environment entailing persistent chronic inflammation and increased levels of COX-2, induced by either duodenogastric reflux or a factor such as H. pylori infection, increases the risk of malignant transformation. Moreover, extra carbonate intake raises the levels of ODC in the gastric mucosa in a COX-2-dependent manner, which magnifies the proliferative drive and results in an even higher risk of gastric carcinoma

Urachal signet-cell adenocarcinoma

This report presents two cases of urachal signet-cell adenocarcinoma (USCA). Two men, aged 53 and 51 years, presented with haematuria. Cystoscopy showed tumours in the dome of the bladder and transurethral resection revealed signet ring cell carcinoma. They both underwent cystoprostatectomy but died of metastatic disease after 14 and 26 months. USCA is a very rare tumour with poor prognosis. Only 25 cases have been reported. The tumours have a specific gross and microscopic morphology but must be distinguished from metastases of signet ring cell originating from other sites. Immunohistochemistry is helpful for the determination of the primary site

Primary seminal vesicle carcinoma detected at transurethral resection of prostate

We present a case of primary seminal vesicle carcinoma detected at transurethral resection. The clinical presentation, radiologic findings, and pathologic features of these tumors are reviewed. Grossly, seminal vesicle carcinoma is poorly circumscribed and solid or solid/cystic and may be misinterpreted as an abscess or hemorrhage on radiologic examination. Although a definitive diagnosis often cannot be given until after complete resection, we describe the findings indicative of seminal vesicle origin, including papillary histologic architecture, sometimes with mucinous differentiation, and a characteristic immunophenotype positive for CA-125 and cytokeratin 7, but negative for prostate-specific antigen and cytokeratin 20. UROLOGY 69: 778.e11-78.e13, 2007

The characterization of epithelial and stromal subsets of candidate stem/progenitor cells in the human adult prostate.

OBJECTIVES: Questions regarding the cell source and mechanisms in the initiation and progression of prostate cancer are today still open for debate. Indeed, our knowledge regarding prostate cell regulation, self-renewal, and cytodifferentiation is presently rather limited. In this study, we investigated these processes in the normal adult human prostate. METHODS: Dynamic expression patterns in prostate stem/progenitor cells, intermediate/transit-amplifying cells, and cell lineages were immunohistochemically identified in an in situ explant renewal model of the human normal/benign adult prostate (n=6). RESULTS: Cells with a basal phenotype proliferated significantly in explant cultures, whereas luminal cells went into apoptosis. Results further show down-regulation in tissue cultures of the basal and hypothetical stem cell marker Bcl-2 in the majority of cells, except in rare putative epithelial stem cells. Investigation of established (AC133) and novel candidate prostate stem/progenitor markers, including the cell surface receptor tyrosine kinase KIT and its ligand stem cell factor (SCF), showed that these rare epithelial cells are AC133(+)/CD133(low)/Bcl-2(high)/cytokeratin(+)/vimentin(-)/KIT(low)/SCF(low). In addition, we report on a stromal population that expresses the mesenchymal marker vimentin and that is AC133(-)/CD133(high)/Bcl-2(-)/cytokeratin(-)/KIT(high)/SCF(high). CONCLUSIONS: We provide evidence for epithelial renewal in response to tissue culture and for basal and epithelial stem/progenitor cell recruitment leading to an expansion of an intermediate luminal precursor phenotype. Data further suggest that SCF regulates prostate epithelial stem/progenitor cells in an autocrine manner and that all or a subset of the identified novel stromal phenotype represents prostate stromal progenitor cells or interstitial pacemaker cells or both

Non-canonical WNT5A signaling up-regulates the expression of the tumor suppressor 15-PGDH and induces differentiation of colon cancer cells

The tumor suppressor 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme in prostaglandin E2 catabolism and is down-regulated in colorectal cancer (CRC) tissue. Canonical Wnt signaling is frequently elevated in colon cancers and has been shown to down-regulate 15-PGDH expression. Therefore, we have in the current study investigated if the non-canonical ligand WNT5A relates to increased expression of 15-PGDH in colon cancer cells. In the same cohort of patients, we demonstrated a parallel and significant loss of 15-PGDH and WNT5A protein expression in CRC tissues compared with matched normal colon tissues. Furthermore, patients with low 15-PGDH/WNT5A expression in their tumors showed reduced survival compared with patients with high 15-PGDH/WNT5A expression. To investigate if WNT5A signaling directly affects 15-PGDH expression, we performed in vitro analyses of colon cancer cells (HT-29 and Caco-2). Both cell lines, when treated with recombinant WNT5A (rWNT5A) or Foxy-5, a WNT5A-mimicking peptide, responded by increasing their expression of 15-PGDH mRNA and protein. Our investigations showed that rWNT5A and Foxy-5 induced this increased expression of 15-PGDH through reduced β-catenin signaling as well as increased JNK/AP-1 signaling in colon cancer cells. WNT5A signaling also induced increased 15-PGDH expression in a breast cancer cell line both in vitro and in vivo. In agreement, WNT5A signaling also increased the expression of the differentiation markers sucrose-isomaltase and mucin-2 in colon cancer cells. Our results show that WNT5A signaling regulates 15-PGDH expression, thus uncovering a novel mechanism by which WNT5A acts as a tumor suppressor and suggests that increased 15-PGDH expression could be used as an indicator of a positive response to Foxy-5 in patients treated with this WNT5A agonist