Intramucosal fat is uncommon in large bowel polyps but raises three differential diagnoses.

AIMS: This case series intends to expand currently limited knowledge regarding the existence and diagnostic significance of intramucosal fat in colorectal polyps. METHODS: Clinicopathological features of nine such polyps were reported following histopathological review, including S100 and EMA immunohistochemistry. RESULTS AND CONCLUSIONS: Such review subdivided seven polyps into three groups: (1) mucosal perineurioma/serrated polyps with fat among the perineurial stroma (three cases); (2) submucosal lipomas with adipose tissue extending into the overlying mucosa (two cases) and (3) polyps with intramucosal adipose tissue only, that is, the newly described but less-recognised entity known as intramucosal lipoma (two cases). The two remaining polyps of this series did not include submucosa but, from assessing their muscularis mucosae, were favoured to represent intramucosal lipomas. The first two phenomena are formally described for the first time by this case series. The last of these three diagnoses should prompt investigations for Cowden syndrome, but intramucosal lipomas are more often sporadic/non-syndromic.

Specific histological abnormalities are more likely in biopsies of endoscopically normal large bowel after the age of 60 years.

AIMS: Colonic and rectal biopsies, often taken from an endoscopically normal large bowel, form a significant proportion of the histopathology workload. The aim of this study was to determine diagnostic yield from mucosal biopsies in patients with normal colonoscopy or sigmoidoscopy, and whether or not diarrhoea is predictive of abnormal histology. METHODS AND RESULTS: A retrospective analysis of pathology requests, endoscopy and pathology reports taken during 1 year was undertaken in a tertiary care hospital for all biopsies from endoscopically normal ileal, colonic and rectal mucosa. Of 626 patients fulfilling inclusion criteria, 602 had at least one colonic or rectal biopsy. Colorectal histology was abnormal in 65 (14.5%) of 447 patients with diarrhoea, while of 155 patients without diarrhoea, histology was abnormal in 17 (11%; P=0.41). Patients older than 60 years had a markedly increased likelihood of a specific histological abnormality [odds ratio 2.76 (1.30-5.79); P=0.0045]. Diagnoses included microscopic colitis, distorted mucosal architecture consistent with inflammatory bowel disease, ischaemia, polyps, mucosal prolapse and schistosomiasis. CONCLUSIONS: Biopsy of an endoscopically normal large bowel, and of the normal terminal ileum in isolation, yields little abnormal histology. Diarrhoea per se does not identify patients at higher risk of abnormal histology. Increased age, however, does, and mucosal biopsy in the endoscopically normal colon and rectum may be more cost-effective in patients aged more than 60 years.

Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy.

Mutations in the androgen receptor (AR) that enable activation by antiandrogens occur in hormone-refractory prostate cancer, suggesting that mutant ARs are selected by treatment. To validate this hypothesis, we compared AR variants in metastases obtained by rapid autopsy of patients treated with flutamide or bicalutamide, or by excision of lymph node metastases from hormone-naïve patients. AR mutations occurred at low levels in all specimens, reflecting genetic heterogeneity of prostate cancer. Base changes recurring in multiple samples or multiple times per sample were considered putative selected mutations. Of 26 recurring missense mutations, most in the NH(2)-terminal domain (NTD) occurred in multiple tumors, whereas those in the ligand binding domain (LBD) were case specific. Hormone-naïve tumors had few recurring mutations and none in the LBD. Several AR variants were assessed for mechanisms that might underlie treatment resistance. Selection was evident for the promiscuous receptor AR-V716M, which dominated three metastases from one flutamide-treated patient. For the inactive cytoplasmically restricted splice variant AR23, coexpression with AR enhanced ligand response, supporting a decoy function. A novel NTD mutation, W435L, in a motif involved in intramolecular interaction influenced promoter-selective, cell-dependent transactivation. AR-E255K, mutated in a domain that interacts with an E3 ubiquitin ligase, led to increased protein stability and nuclear localization in the absence of ligand. Thus, treatment with antiandrogens selects for gain-of-function AR mutations with altered stability, promoter preference, or ligand specificity. These processes reveal multiple targets for effective therapies regardless of AR mutation.

Profiling human androgen receptor mutations reveals treatment effects in a mouse model of prostate cancer.

Gain-of-function mutations in the androgen receptor (AR) are found in prostate cancer and are implicated in the failure of hormone therapy. Most studies have emphasized the ligand-binding domain (LBD) where mutations can create promiscuous receptors, but mutations in the NH(2)-terminal transactivation domain have also been found. To assess AR alteration as a mechanism of treatment resistance, a mouse model (h/mAR-TRAMP) was used in which the murine AR coding region is replaced by human sequence and prostate cancer initiated by a transgenic oncogene. Mice received either no treatment, androgen depletion by castration, or treatment with antiandrogens, and 20 AR transcripts were sequenced per end-stage tumor. All tumors expressed several mutant alleles, although most mutations were low frequency. Some mutations that occurred multiple times within the population were differentially located dependent on treatment. Mutations in castrated or antiandrogen-treated mice were widely dispersed but with a prominent cluster in the LBD (amino acids 736-771), whereas changes in intact mice centered near the NH(2)-terminal polymorphic glutamine tract. Functional characterization of selected LBD mutant alleles showed diverse effects on AR activity, with about half of the mutations reducing transactivation in vitro. One receptor, AR-R753Q, behaved in a cell- and promoter-dependent manner, although as a germ-line mutation it causes androgen insensitivity syndrome. This suggests that alleles that are loss of function during development may still activate a subset of AR targets to become gain of function in tumorigenesis. Mutant ARs may thus use multiple mechanisms to evade cancer treatment.

Androgen receptor variants and prostate cancer in humanized AR mice.

Androgen, acting via the androgen receptor (AR), is central to male development, differentiation and hormone-dependent diseases such as prostate cancer. AR is actively involved in the initiation of prostate cancer, the transition to androgen independence, and many mechanisms of resistance to therapy. To examine genetic variation of AR in cancer, we created mice by germ-line gene targeting in which human AR sequence replaces that of the mouse. Since shorter length of a polymorphic N-terminal glutamine (Q) tract has been linked to prostate cancer risk, we introduced alleles with 12, 21 or 48 Qs to test this association. The three "humanized" AR mouse strains (h/mAR) are normal physiologically, as well as by cellular and molecular criteria, although slight differences are detected in AR target gene expression, correlating inversely with Q tract length. However, distinct allele-dependent differences in tumorigenesis are evident when these mice are crossed to a transgenic prostate cancer model. Remarkably, Q tract variation also differentially impacts disease progression following androgen depletion. This finding emphasizes the importance of AR function in androgen-independent as well as androgen-dependent disease. These mice provide a novel genetic paradigm in which to dissect opposing functions of AR in tumor suppression versus oncogenesis.

Glutamine tract length of human androgen receptors affects hormone-dependent and -independent prostate cancer in mice.

The androgen receptor (AR) is involved in the initiation and progression of prostate cancer and its transition to androgen independence. Genetic variation in AR may contribute to disease risk and has been studied for a polymorphic N-terminal glutamine (Q) tract that shows population heterogeneity. While the length of this tract is known to affect AR in vitro, association with disease is complicated by genetic and environmental factors that have led to discordant epidemiological findings. To clarify the effect of Q tract polymorphism on prostate cancer, we created mice bearing humanized AR genes (h/mAr) varying in Q tract length. ARs with short Q tracts (12Q), which are transcriptionally more active, induce earlier disease in the transgene-induced TRAMP prostate cancer model than alleles with median (21Q) or long (48Q) tracts. Disease length varies within each genotype, with greater differentiation and AR expression in slower growing tumors. Remarkably, following androgen ablation, Q tract length has effects that are also allele-dependent and in directions opposite to those in hormone intact mice. Differences in AR activity conferred by Q tract length thus appear to direct distinct pathways of androgen-independent as well as androgen-dependent progression, and highlight substantial risk that may be associated with alterations in the androgen axis. This AR allelic series in humanized mice provides an experimental paradigm to dissect the role of AR in prostate cancer initiation and progression, to model response to treatment and to test therapies targeted specifically to the human AR.

Synthesis and secretion of angiotensin II by the prostate gland in vitro.

The renin angiotensin system has been shown to have tissue-related functions that are distinct from its systemic roles. We showed that angiotensin II type 1 (AT1) receptors are present in mammalian sperm, and angiotensin II stimulates sperm motility and capacitation. In addition, angiotensin II is present in human seminal plasma at concentrations higher than found in blood. In testing the possibility that the prostate may be the source of seminal plasma angiotensin II, mRNA coding for angiotensinogen, (pro)renin, and angiotensin-converting enzyme were identified by RT-PCR in rat and human prostate and in prostate LNCaP cells, as well as the angiotensin receptors types 1 and 2 (AT1 and AT2) in human tissues and AT1 in rat. In human tissue, immunocytochemistry showed cellular colocalization of renin with the AT1 receptor in secretory epithelial cells. Confirmation of the capacity of the prostate to secrete angiotensin II was shown by the detection of immunoreactive angiotensin in media removed from rat prostate organ cultures and LNCaP cells. Rat prostate angiotensin secretion was enhanced by dihydrotestosterone, but LNCaP angiotensin was stimulated by estradiol. This stimulation was blocked by tamoxifen. Rat prostate AT1 receptor expression was much greater in prepuberal than in postpuberal rats but was not affected by a low-sodium diet. It was, however, significantly enhanced by captopril pretreatment. These findings all suggest the independence of prostate and systemic renin angiotensin system regulation. The data presented here suggest that the prostate may be a source of the secreted angiotensin II found in seminal plasma.