ß2 -adrenergic receptor signaling drives prostate cancer progression by targeting the Sonic hedgehog-Gli1 signaling activation.

BACKGROUND: Considerable evidence suggests that the sympathetic nervous system, mainly via adrenergic signaling, contributes to prostate cancer (PCa) progression. However, the underlying molecular mechanisms remain unknown. METHODS: The expression level of ß2 -adrenergic receptor (ß2 -AR) in tissue microarray was evaluated by immunohistochemistry. The effects of isoproterenol (ISO) or Sonic Hedgehog (Shh) signaling inhibitor on tumor growth were analyzed in proliferation and colony formation assays. The apoptosis of cells was analyzed by flow cytometry. Small hairpin RNA-based knockdown of ß2 -AR or Gli1 was validated by Western blot analysis and real-time PCR. Effects of ß2 -AR on prostate carcinogenesis in vivo were observed in a mouse xenograft model. The expression levels of the indicated proteins in xenograft tissues were evaluated by immunohistochemistry. Expression levels of Shh signaling components and downstream proteins were assessed by immunoblotting. RESULTS: We determined that ß2 -AR was expressed at significantly higher levels in carcinoma than in normal prostate tissues. ß2 -AR signaling also played an essential role in sustaining PCa cell proliferation in vivo and in vitro. We also found that inhibition of Shh signaling or knockdown of Gli1 expression significantly restrained ISO-induced cell proliferation in vitro. ISO alleviated the apoptosis induced by suppressing or knocking down of Gli1. The ß2 -AR agonist ISO upregulated the transcription and protein expression of target genes of Shh signaling, including c-Myc, Cyclin D1, and VEGFA. Conversely, knocking down ß2 -AR markedly suppressed the expression of Shh components in vivo and in vitro. In Gli1 knockdown cells, ISO failed to increase the expression of target genes of Shh signaling. CONCLUSIONS: In this study, we uncovered an important role of ß2 -AR signaling in regulating the Shh pathway activity in PCa tumorigenesis and provide further insight into the mechanism of the involvement of the Hh signaling pathway. Furthermore, given the efficacy of ß2 -adrenergic modulation on PCa, our study might also add evidence for potential therapeutic options of ß-blockers for PCa.

Extramural depth of tumor invasion at thin-section MR in rectal cancer: associating with prognostic factors and ADC value.

PURPOSE: To assess the value of maximal extramural depth (EMD) of T3 tumor spread on MRI as a potential noninvasive imaging biomarker of tumor aggressiveness in rectal cancer, by analyzing the relationship between tumoral EMD values and clinical or histological prognostic parameters. In addition, we try to investigate the relationship between EMD and apparent diffusion coefficient (ADC) values. MATERIALS AND METHODS: Ninety rectal cancer patients who underwent primary MRI staging and diffusion weighted imaging (DWI) as T3 tumor were included. Tumor EMD was measured, and the EMD values of the subgroups based on pretreatment CEA, CA19-9 levels, N stage, and histological parameters were compared. The correlation between EMD and ADC values was compared. RESULTS: Interobserver agreement of confidence levels for observers 1 and 2 was good for cN stage (k = 0.678) and EMD measurement(k = 0.612) and was excellent for ADC measurement (k = 0.880). Tumor EMDs differ between CEA <5 ng/mL versus ≥ 5 ng/mL (P = 0.013), CA19-9 < 27 U/mL versus ≥ 27 U/mL (P = 0.012), the groups of cN0 versus cN+ cancers (P = 0.049), and between the several groups of histological differentiation grades (P = 0.033). There was no significant difference in EMDs between the various groups of vessel carcinoma embolus and neural invasion. A significant negative correlation (r = -0.581; P = 0.001) between ADC and EMD values was found. CONCLUSION: Significant correlations were found between EMD values and CEA, CA19-9 level, differentiation grade and ADC value. As been found, higher EMD values were associated with a more aggressive tumor profile and, therefore, EMD has the potential to become an imaging biomarker of tumor aggressiveness indicator.

[Diagnostic value of full-field digital mammography for breast carcinoma].

OBJECTIVE: To evaluate the diagnostic value of full-field digital mammography for breast cancer. METHODS: The clinical data and mammograms of 230 patients with breast diseases between January 2008 and July 2008 were collected and reviewed. Craniocaudal (CC) and mediolateral oblique (MLO) view mammograms were performed in all patients before surgery. Three experienced radiologists in breast imaging assessment analyzed and classified all the mammograms according to breast imaging reporting and data system (BI-RADS). The sensitivity, specificity and accuracy were evaluated according to their pathological diagnosis. The reasons resulting in false-negative and false-positive diagnosis were also analyzed. RESULTS: Of the 238 samples, 130 had a malignant breast tumors and 108 cases of benign breast lesions. One hundred and nine of the 130 malignant breast tumors were invasive ductal carcinoma. Fifty-seven of the 108 benign breast lesions were breast adenosis. Masses or masses with microcalcification were the most frequently seen signs of the malignant tumors, accounting for 40.8% and 20.8%, respectively. The sensitivity, specificity and accuracy of FFDM in detecting breast carcinoma were 90.8%, 87.0% and 89.1%, respectively. The false-negative signs including negative X-ray finding (5 cases) and focal asymmetric densities (4 cases). The false-positive signs were masses with spiculate, indistinctive or lobulated margin leading to misdiagnosing the lesions as malignant tumors. CONCLUSION: Full-field digital mammography (FFDM) is helpful in detection of breast cancers in women, with a higher sensitivity, specificity and accuracy, and has an important clinical application value.

Muscarinic acetylcholine receptor M1 mediates prostate cancer cell migration and invasion through hedgehog signaling.

The autonomic nervous system contributes to prostate cancer proliferation and metastasis. However, the exact molecular mechanism remains unclear. In this study, muscarinic acetylcholine receptor M1 (CHRM1) expression was measured via immunohistochemical analysis in human prostate cancer tissue array slides. PC-3, LNCaP, and A549 cells were treated with pirenzepine or carbachol, and the cell migration and invasion abilities were evaluated. Western blotting and quantitative real-time PCR were performed to measure GLI family zinc finger 1 (GLI1), patched 1 (PTCH1), and sonic hedgehog (SHH) expression levels. High expression of CHRM1 was found in early-stage human prostate cancer tissues. In addition, the selective CHRM1 antagonist pirenzepine inhibited PC-3, LNCaP, and A549 cell migration and invasion, but the agonist carbachol promoted the migration and invasion of these three cell lines. Muscarinic signaling can be relayed by hedgehog signaling. These data show that CHRM1 is involved in the regulation of prostate cancer migration and invasion through the hedgehog signaling pathway.