MiRNA-21 Expression Decreases from Primary Tumors to Liver Metastases in Colorectal Carcinoma.

OBJECTIVE Metastasis is the major cause of death in colorectal cancer patients. Expression of certain miRNAs in the primary tumors has been shown to be associated with progression of colorectal cancer and the initiation of metastasis. In this study, we compared miRNA expression in primary colorectal cancer and corresponding liver metastases in order to get an idea of the oncogenic importance of the miRNAs in established metastases. METHODS We analyzed the expression of miRNA-21, miRNA-31 and miRNA-373 in corresponding formalin-fixed paraffin-embedded (FFPE) tissue samples of primary colorectal cancer, liver metastasis and healthy tissues of 29 patients by quantitative real-time PCR. RESULTS All three miRNAs were significantly up-regulated in the primary tumor tissues as compared to healthy colon mucosa of the respective patients (p < 0.01). MiRNA-21 and miRNA-31 were also higher expressed in liver metastases as compared to healthy liver tissues (p < 0.01). No significant difference of expression of miRNA-31 and miRNA-373 was observed between primary tumors and metastases. Of note, miRNA-21 expression was significantly reduced in liver metastases as compared to the primary colorectal tumors (p < 0.01). CONCLUSION In the context of previous studies demonstrating increased miRNA-21 expression in metastatic primary tumors, our findings raise the question whether miRNA-21 might be involved in the initiation but not in the perpetuation and growth of metastases

Prognostic value of β1 integrin expression in colorectal liver metastases

Integrins are cell surface adhesion molecules (CAM) that regulate via intercellular and cell-matrix signaling various cellular processes including wound healing, cell differentiation, division, growth, migration and metastatic dissemination. Although a correlation between carcinogenesis and changes in integrin expression, especially β1 integrin, has been reported, its role in colorectal liver metastases remains unclear. This study aimed to evaluate the expression of β1 integrin in colorectal liver metastases and to correlate the pattern of expression with clinicopathological features and to investigate the putative role of β1 integrin expression on survival of these patients. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor samples of 81 patients who were operated because of colorectal liver metastases without any neoadjuvant therapy were obtained and stained with hematoxylin and eosin (H & E). An immunohistochemical examination was performed using Dako, Peroxidase/DAB kit and a primary monoclonal β1 integrin (CD29, fibronectin receptor subunit beta; ab3167, Abcam plc). β1 integrin expression was evaluated according to the immunoreactive score of Remmele and Stegner and was related with clinicopathological features of prognostic significance and with disease-free and overall survival as well. Statistical analysis was performed using SPSS version 21.0. Results: β1 integrin was overexpressed in tumor cells in 37 (48%) patients and in stromal cell in 27 (33%) patients. The β1 expression was not statistically correlated with clinicopathological features of the primary tumors but it was statistically correlated (p=0.03) with the histological grading of liver metastases. Kaplan-Meier survival analysis showed that there is a tendency but no statistically significant correlation in disease-free and overall survival. Conclusion: Considering that expression of β1 integrin in colorectal liver metastases remains controversial, specially its relation with survival of patients, we showed that the β1 expression represents a reliable prognostic factor regarding the grading of liver metastases of CRC and our findings imply that β1 integrin expression profiles may have further potential in identifying the stage of colorectal liver metastases and being a marker of prognosis in these patients

MiRNA-21 Expression Decreases from Primary Tumors to Liver Metastases in Colorectal Carcinoma

Objective Metastasis is the major cause of death in colorectal cancer patients. Expression of certain miRNAs in the primary tumors has been shown to be associated with progression of colorectal cancer and the initiation of metastasis. In this study, we compared miRNA expression in primary colorectal cancer and corresponding liver metastases in order to get an idea of the oncogenic importance of the miRNAs in established metastases. Methods We analyzed the expression of miRNA-21, miRNA-31 and miRNA-373 in corresponding formalin-fixed paraffin-embedded (FFPE) tissue samples of primary colorectal cancer, liver metastasis and healthy tissues of 29 patients by quantitative real-time PCR. Results All three miRNAs were significantly up-regulated in the primary tumor tissues as compared to healthy colon mucosa of the respective patients (p < 0.01). MiRNA-21 and miRNA-31 were also higher expressed in liver metastases as compared to healthy liver tissues (p < 0.01). No significant difference of expression of miRNA-31 and miRNA-373 was observed between primary tumors and metastases. Of note, miRNA-21 expression was significantly reduced in liver metastases as compared to the primary colorectal tumors (p < 0.01). Conclusion In the context of previous studies demonstrating increased miRNA-21 expression in metastatic primary tumors, our findings raise the question whether miRNA-21 might be involved in the initiation but not in the perpetuation and growth of metastases

Olaparib is effective in combination with, and as maintenance therapy after, first‐line endocrine therapy in prostate cancer cells

A number of prostate cancer (PCa)‐specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor olaparib used as single agent for treatment of metastatic castration‐resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa, we evaluated a potential use for olaparib in combination with first‐line endocrine treatments, androgen deprivation, and complete androgen blockade, and as a maintenance therapy following on from endocrine therapy. We demonstrate that the LNCaP cell line, possessing multiple aberrations in BRCAness genes, is sensitive to olaparib. Additive effects of olaparib combined with endocrine treatments in LNCaP are noted. In contrast, we find that the TMPRSS2:ERG fusion‐positive cell lines VCaP and DuCaP do not show signs of synthetic lethality, but are sensitive to cytotoxic effects caused by olaparib. In consequence, additive effects of olaparib with endocrine therapy were not observable in these cell lines, showing the need for synthetic lethality in combination treatment regimens. Additionally, we show that PCa cells remain sensitive to olaparib treatment after initial androgen deprivation implicating a possible use of olaparib as maintenance therapy. In sum, our preclinical data recommend olaparib as a synthetic lethal treatment option in combination or sequenced to first‐line endocrine therapy for PCa patients with diagnosed BRCAness

Correlation of miRNA-21 to patient follow-up.

<p>Disease-free survival with regard to liver metastasis (LiMe) and overall survival illustrated with the Kaplan-Meier method. <b>(a)</b> Comparison of overall survival between a miRNA-21 high and low expression group in colorectal carcinomas (PrTu). There is a trend towards shorter survival with higher miRNA-21 levels, although not significant (p = 0.27). <b>(b)</b> The patients with metachronous LiMe are sub-divided into a high and low miRNA-21 expression group in PrTu. By trend, high miRNA-21 led to earlier manifestation of LiMe (p = 0.20). <b>(c)</b> A comparison of survival between a high and a low miRNA-21 group in LiMe shows no significant difference (p = 0.44). <b>(d)</b> Survival does not differ significantly between those patients with higher miRNA-21 in the primary tumor and those with higher miRNA-21 in LiMe.</p

MiRNA expression levels in primary tumors, metastases and corresponding normal tissues of patients with colorectal carcinoma.

<p><b>(a)–(i)</b> Aggregated box-plot comparisons of miRNA-31, miRNA-373 and miRNA-21 expression levels. All miRNAs are significantly higher expressed in colorectal carcinomas (PrTu) than in healthy colorectal mucosa (HeMu) <b>(a, d, g)</b>. Expression in liver metastases (LiMe) is significantly higher than in healthy liver tissue (HeLi) for miRNA-31 <b>(b)</b> and miRNA-21 <b>(h)</b>. A comparison of PrTu and LiMe shows significantly higher miRNA-21 in the primary tumor tissue (<b>i</b>; p < 0.01). MiRNA-31 is higher by trend (<b>c</b>; p = 0.09). <b>(j)–(l)</b> MiRNA-21 expression is compared on a combined intra- and inter-patient level over the same tissues. Expression levels in one patient are represented by two dots connected by a line. As for the comparison of PrTu and HeMu <b>(j)</b> and LiMe and HeLi <b>(k)</b>, respectively, in > 95% and about 90% of the patients, there is more miRNA-21 in the respective tumor than in the healthy tissues. <b>(l)</b> Comparison of miRNA-21 in PrTu and LiMe: 21 of 29 patients show higher miRNA-21 levels in the primary tumor. ** indicates p < 0.01.</p

Patient characteristics.

<p>Patient characteristics.</p

MiRNA-21 Expression Decreases from Primary Tumors to Liver Metastases in Colorectal Carcinoma

<div><p>Objective</p><p>Metastasis is the major cause of death in colorectal cancer patients. Expression of certain miRNAs in the primary tumors has been shown to be associated with progression of colorectal cancer and the initiation of metastasis. In this study, we compared miRNA expression in primary colorectal cancer and corresponding liver metastases in order to get an idea of the oncogenic importance of the miRNAs in established metastases.</p><p>Methods</p><p>We analyzed the expression of miRNA-21, miRNA-31 and miRNA-373 in corresponding formalin-fixed paraffin-embedded (FFPE) tissue samples of primary colorectal cancer, liver metastasis and healthy tissues of 29 patients by quantitative real-time PCR.</p><p>Results</p><p>All three miRNAs were significantly up-regulated in the primary tumor tissues as compared to healthy colon mucosa of the respective patients (p < 0.01). MiRNA-21 and miRNA-31 were also higher expressed in liver metastases as compared to healthy liver tissues (p < 0.01). No significant difference of expression of miRNA-31 and miRNA-373 was observed between primary tumors and metastases. Of note, miRNA-21 expression was significantly reduced in liver metastases as compared to the primary colorectal tumors (p < 0.01).</p><p>Conclusion</p><p>In the context of previous studies demonstrating increased miRNA-21 expression in metastatic primary tumors, our findings raise the question whether miRNA-21 might be involved in the initiation but not in the perpetuation and growth of metastases.</p></div

Dataset for: Olaparib is effective in combination with, and as maintenance therapy after, first-line endocrine therapy in prostate cancer cells.

A number of prostate cancer (PCa)-specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor Olaparib used as single agent for treatment of metastatic castration-resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa we evaluated a potential use for Olaparib in combination with first-line endocrine treatments, androgen deprivation and complete androgen blockade and as a maintenance therapy sequenced to endocrine therapy. We demonstrate that the LNCaP cell line possessing multiple aberrations in BRCAness genes is sensitive to Olaparib. Additive effects of Olaparib combined to endocrine treatments in LNCaP are noted. In contrast, we find that the TMPRSS2:ERG-fusion positive cell lines VCaP and DuCaP do not show signs of synthetic lethality, but are sensitive to cytotoxic effects caused by Olaparib. In consequence, additive effects of Olaparib with endocrine therapy were not observable in these cell lines, showing the need for synthetic lethality in combination treatment regimens. Additionally, we show that PCa cells remain sensitive to Olaparib treatment after initial androgen deprivation implicating a possible use of Olaparib as maintenance therapy. In sum, our pre-clinical data recommend Olaparib as a synthetic lethal treatment option in combination or sequenced to first-line endocrine therapy for PCa patients with diagnosed BRCAness