Downregulation of RIZ1 protein expression in left-sided versus right-sided primary colorectal carcinomas and their distant metastases and the association with NF-B activation

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15112-e15112
Author(s):  
E. Torlakovic ◽  
E. C. Marginean ◽  
G. Torlakovic ◽  
R. Geyer ◽  
H. Neufeld ◽  
...  
Keyword(s):  
Protein Expression ◽  
Colorectal Adenocarcinoma ◽  
Nuclear Translocation ◽  
Human Cancer ◽  
Distant Metastases ◽  
Normal Mucosa ◽  
Metastatic Carcinoma ◽  
Chi Square ◽  
Primary Tumors ◽  
Molecular Events

e15112 Background: Activation of NF- B leads to enhanced proliferation and the expression of anti-apoptotic proteins, which are cancer phenotypes. RIZ1 inactivation through various molecular events was linked to increased proliferation, migration induction and apoptosis inhibition in human cancer. RIZ1 frameshift mutations were recently reported to be confined to MSI-H colorectal tumors and proximal tumor origin, while its hypermethylation was not limited to MSI-H tumors. However, RIZ1 protein expression has not been evaluated in colorectal carcinoma. Methods: TMAs included 28 left-sided and 12 right-sided primary colorectal adenocarcinomas, their matched normal mucosa and their respective distant metastases. Left-sided tumors were compared to right-sided tumors for expression of RIZ1 protein and NF- B activation. RIZ1 immunostaining was scored semiquantitatively (0–3+). NF- B activation was determined by IHC detecting nuclear translocation of its p65 subunit in more than 30% tumor nuclei. Discrepant results were defined as score difference of 2. Results: RIZ1 was less expressed in tumors than in benign mucosa (p<0.0001, r=- 0.377, Chi-Square). The difference between primary vs. metastatic carcinoma was not significant. Low RIZ1 was associated with NF- B activation (p<0.0001, Linear-by-Linear). Left-sided primary tumors showed less RIZ1 protein expression than right-sided (p=0.03, Chi-Square). NF- B activation was more frequent in left-sided primary tumors and their respective metastases (35% in right vs. 67% in left; p=0.002, Chi-Square Test). RIZ1 expression and NF- B activation were almost identical in primary and their respective metastatic tumors with only 3 discrepant results for NF- B status and 2 discrepant results in RIZ1 expression. Conclusions: While RIZ1 downregulation in colorectal adenocarcinoma due to RIZ1 mutations appears to be associated with MSI-H and proximal origin, its protein expression appears to be downregulated more often in distal tumors. NF- B activation is strongly associated with lower RIZ1 protein expression in colorectal adenocarcinoma. No significant financial relationships to disclose.

Association of upregulated GATA-4 transcription factor colorectal adenocarcinoma with metastatic and primary tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15093-e15093
Author(s):  
E. C. Marginean ◽  
G. Torlakovic ◽  
H. Neufeld ◽  
E. Torlakovic
Keyword(s):  
Transcription Factor ◽  
Cancer Progression ◽  
Colonic Mucosa ◽  
Colorectal Adenocarcinoma ◽  
Human Cancer ◽  
Positive Association ◽  
Experimental Models ◽  
Normal Colonic Mucosa ◽  
Chi Square ◽  
Primary Tumors

e15093 Background: GATA-4 zinc finger transcription factor is involved in regulation of cellular development, proliferation, and differentiation and is important in embryonic development of gastrointestinal tract. However, GATA-4 is not expressed in normal adult colonic mucosa. Its protein expression in colonic adenocarcinoma has not been systematically evaluated and small number of samples was previously reported as negative. Nuclear factor-B (NF-B) activation was shown to promote the growth of the colon tumors in experimental models and was correlated with tumor angiogenesis and progression in human colorectal cancer. Methods: Forty cases of colorectal adenocarcinoma were evaluated. The benign colonic mucosa and the matching metastatic tumors of the same patients were also included in the study. TMAs which included 139 samples were evaluated by immunohistochemistry and nuclear and cytoplasmic GATA-4 expression was scored (0–3+). NF-B activation was detected as nuclear reactivity for p65. Results: GATA-4 was expressed in 32% of colorectal adenocarcinoma, but not in benign colonic mucosa (p=0.0001, Chi-Square). GATA-4 was also significantly more expressed in metastatic (41%) than in primary (21%) colorectal adenocarcinoma (p<0.0001, Chi-Square). NF-B activation was not present in any of the samples of benign colonic mucosa, but it was detected in 64% adenocarcinomas (p<0.0001, Chi-Square). While there was no difference in NF-B activation between primary vs. metastatic adenocarcinoma, a strong positive association between GATA-4 expression and NF-B activation (p<0.0001, Linear-by- Linear) was found. Conclusions: GATA-4, a developmental transcription factor is not expressed by normal colonic mucosa, but is present in 1/5 of primary tumors that gave rise to distant metastases and in almost 1/2 of their respective metastases. GATA- 4 is also strongly positively associated with NF-B activation previously described to have a role in human cancer progression. GATA-4 may have a role in colorectal adenocarcinoma development and progression and it should be further evaluated in prospective studies as a putative adverse prognostic factor in colorectal adenocarcinoma. No significant financial relationships to disclose.

Deleted in Colon Cancer Protein Expression in Colorectal Cancer Metastases: A Major Predictor of Survival in Patients With Unresectable Metastatic Disease Receiving Palliative Fluorouracil-Based Chemotherapy

2004 ◽  
Vol 22 (18) ◽  
pp. 3758-3765 ◽  
Author(s):  
Carlo Aschele ◽  
Domizia Debernardis ◽  
Sara Lonardi ◽  
Roberto Bandelloni ◽  
Stefania Casazza ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Protein Expression ◽  
Regional Lymph Node ◽  
Survival Rates ◽  
Distant Metastases ◽  
Patient Characteristics ◽  
Rank Test ◽  
Primary Tumors ◽  
Major Predictor

Purpose To determine whether deleted in colon cancer (DCC) protein expression in colorectal cancer (CRC) metastases could predict outcome to palliative fluorouracil (FU)-based chemotherapy and to assess whether it is similar to that observed in the corresponding primary tumors. Patients and Methods DCC protein expression was assessed immunohistochemically on archival specimens of CRC metastases from 42 patients homogeneously treated by methotrexate-modulated bolus FU alternated to 6-S-leucovorin–modulated infused FU and was retrospectively correlated with patient characteristics and clinical outcome. In a subset analysis, DCC immunoreactivity was compared between metastatic CRC and the corresponding primary tumors and regional lymph node metastases. Results Positive immunoreactivity for DCC was found in 45% of patients. Eighteen (78%) of 23 patients for whom multiple samples were available displayed a similar pattern of expression in distant metastases and primary tumors. The median survival time was 14.3 months in patients without DCC expression and 21.4 months in patients with DCC-positive tumors (log-rank test, P = .04); the 2-year survival rates were 8.5% and 42.5%, respectively. Response rates to chemotherapy were not significantly different between the two groups. By multivariate analysis, DCC protein expression maintained its prognostic value and showed to be the single best predictor of survival, with a relative risk of 2.16. Conclusion Our results indicate that expression of the DCC protein in CRC metastases is similar to that observed in the corresponding primary tumors and represents a dominant predictor of survival in patients with unresectable, advanced CRC who are undergoing palliative FU-based chemotherapy.

Frequency of discordance in programmed death ligand 1 (PD-L1) expression between primary tumors and paired distant metastases in advanced cancers: A systematic review and meta-analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14290-e14290
Author(s):  
Chia Ching Lee ◽  
Ivan Weng Keong Tham ◽  
Char Loo Tan ◽  
Jeffrey Lum ◽  
Jeremy Chee Seong Tey ◽  
...  
Keyword(s):  
Primary Tumor ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Distant Metastases ◽  
P Value ◽  
Significant Heterogeneity ◽  
Chi Square ◽  
Primary Tumors ◽  
Methodologic Quality ◽  
Discordance Rate

e14290 Background: Randomized trials have demonstrated that PD-L1 expression in tumor cells predicts for response to PD-1 or PD-L1 checkpoint inhibitors in advanced cancers. However, the frequency of discordance in PD-L1 expression between primary tumors and paired distant metastases is currently unclear. We aimed to determine the discordance rate of PD-L1 expression between primary tumor and paired distant metastases in advanced cancers. Methods: We searched MEDLINE and EMBASE for eligible studies. We noted the discordance rate (positive-to-negative or vice versa) and performed subgroup analyses based on the PD-L1 expression in primary tumor, locations of primary tumor and distant metastases, positivity thresholds and type of antibody used for testing. We used QUADAS-2 tool to assess the methodologic quality of the included studies. We performed the meta-analysis using the logistic-normal random effects model. Results: We identified 11 eligible studies including 351 cases of lung, colorectal, breast and ovarian cancers. Nine studies were judged to have low risk of bias in their methodological quality. The overall discordance rate in PD-L1 expression between primary tumor and paired distant metastases was 28% (95% confidence interval (CI) = 18-41) with significant heterogeneity among the studies (chi-square test P-value < 0.0001). There was no statistically significant differences in discordance rates between the subgroups: PD-L1-positive (40%, 95% CI = 21-63) vs PD-L1-negative primary tumors (21%, 95% CI = 12-34), lung primary (31%, 95% CI = 14-55) vs colorectal/ breast/ ovarian primary (27%, 95% CI = 19-37), central nervous system metastases (22%, 95% CI = 8-47) vs liver/ lung/ pleural/ peritoneum metastases (34%, 95% CI = 24-46); 1% (23%, 95% CI 16-33) vs 5% positivity threshold (33%, 95% CI 11-68); E1L3N (42%, 95% CI 10-82) vs SP142 antibody (27%, 95% CI 20-36). Conclusions: The discordance in PD-L1 expression between primary tumors and paired distant metastases is close to 30%, which could potentially affect response to immunotherapy. Further works exploring the mechanisms and impact of this discordance are warranted.

scholarly journals The levels of sICAM-1, sELAM-1, TNFα and sTNFR1 proteins in patients with colorectal adenocarcinoma in tumor and corresponding normal mucosa

2020 ◽  
Author(s):  
Joanna K. Strzelczyk ◽  
Piotr Cuber ◽  
Benjamin Bochon ◽  
Krzysztof Gajdzik ◽  
Janusz Strzelczyk ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Colorectal Adenocarcinoma ◽  
Cancer Survival ◽  
Distant Metastases ◽  
Normal Mucosa ◽  
Protein Levels ◽  
Tissue Homogenates ◽  
Clinical Profiles ◽  
Tissue Specimens

Colorectal cancer is a common malign disease of the gastrointestinal tract. The cancer survival rate depends on the stage of the disease at detection time. It is well known that several molecular mechanisms are involved in cancer and some molecules might affect or modulate neogenesis. The aim of the study was to assess the levels of sICAM-1, sELAM-1, TNFα and sTNFR1 protein in tumor and corresponding normal mucosa in a group of patients with colorectal adenocarcinoma and also associations of these parameters with demographic and clinical profiles of the patients. Tissue specimens were obtained during resection of neoplastic lesions. Protein levels were assayed in tissue homogenates by ELISA. The protein level of sICAM-1 in tumor was significantly increased in comparison to the corresponding normal mucosa (80.06 ng/mg vs 69.53 ng/mg, p=0.02). Furthermore, a significant positive correlation between sICAM-1 and sTNFR1 proteins levels in tumor (rs=0.58, p<0.001) and in corresponding normal mucosa (rs=0.48, p<0.001) was found. Also, significant correlations in corresponding normal mucosa were found between sELAM-1 and sICAM-1 (rs=0.58, p<0.001) and between sTNFR1 and sELAM-1 (rs=0.57, p<0.001). Significantly higher level of sTNFR1 in corresponding normal mucosa samples of patients with distant metastases was observed (p=0.04). Obtained results suggest that sICAM-1 protein could be considered as colorectal cancer marker. Furthermore, sTNFR1 also has the potential to become a good prognostic marker used during monitoring of the patients. Nevertheless, a further study in this area to confirm this correlation is required.

scholarly journals Expression of the Chemokine Receptor CCR7 in the Normal Adrenal Gland and Adrenal Tumors and Its Correlation with Clinical Outcome in Adrenocortical Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5693
Author(s):  
Carmina Teresa Fuss ◽  
Katharina Other ◽  
Britta Heinze ◽  
Laura-Sophie Landwehr ◽  
Armin Wiegering ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Protein Expression ◽  
Chemokine Receptor ◽  
Adrenocortical Carcinoma ◽  
Distant Metastases ◽  
Adrenal Tumors ◽  
Mrna Levels ◽  
Primary Tumors ◽  
Adrenocortical Tumors ◽  
Adrenocortical Adenomas

Background: The chemokine receptor CCR7 is crucial for an intact immune function, but its expression is also associated with clinical outcome in several malignancies. No data exist on the expression of CCR7 in adrenocortical tumors. Methods: CCR7 expression was investigated by qRT-PCR and immunohistochemistry in 4 normal adrenal glands, 59 adrenocortical adenomas, and 181 adrenocortical carcinoma (ACC) samples. Results: CCR7 is highly expressed in the outer adrenocortical zones and medulla. Aldosterone-producing adenomas showed lower CCR7 protein levels (H-score 1.3 ± 1.0) compared to non-functioning (2.4 ± 0.5) and cortisol-producing adenomas (2.3 ± 0.6), whereas protein expression was variable in ACC (1.8 ± 0.8). In ACC, CCR7 protein expression was significantly higher in lymph node metastases (2.5 ± 0.5) compared to primary tumors (1.8±0.8) or distant metastases (2.0 ± 0.4; p < 0.01). mRNA levels of CCR7 were not significantly different between ACCs, normal adrenals, and adrenocortical adenomas. In contrast to other tumor entities, neither CCR7 protein nor mRNA expression significantly impacted patients’ survival. Conclusion: We show that CCR7 is expressed on mRNA and protein level across normal adrenals, benign adrenocortical tumors, as well as ACCs. Given that CCR7 did not influence survival in ACC, it is probably not involved in tumor progression, but it could play a role in adrenocortical homeostasis.

scholarly journals Chromatin accessibility associates with protein-RNA correlation in human cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Akshay Sanghi ◽  
Joshua J. Gruber ◽  
Ahmed Metwally ◽  
Lihua Jiang ◽  
Warren Reynolds ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Chromatin Structure ◽  
Human Cancer ◽  
Chromatin Accessibility ◽  
Human Thyroid ◽  
Breast Cancers ◽  
Primary Tumors ◽  
Highly Correlated ◽  
Molecular Phenotypes

AbstractAlthough alterations in chromatin structure are known to exist in tumors, how these alterations relate to molecular phenotypes in cancer remains to be demonstrated. Multi-omics profiling of human tumors can provide insight into how alterations in chromatin structure are propagated through the pathway of gene expression to result in malignant protein expression. We applied multi-omics profiling of chromatin accessibility, RNA abundance, and protein abundance to 36 human thyroid cancer primary tumors, metastases, and patient-match normal tissue. Through quantification of chromatin accessibility associated with active transcription units and global protein expression, we identify a local chromatin structure that is highly correlated with coordinated RNA and protein expression. In particular, we identify enhancers located within gene-bodies as predictive of correlated RNA and protein expression, that is independent of overall transcriptional activity. To demonstrate the generalizability of these findings we also identify similar results in an independent cohort of human breast cancers. Taken together, these analyses suggest that local enhancers, rather than distal enhancers, are likely most predictive of cancer gene expression phenotypes. This allows for identification of potential targets for cancer therapeutic approaches and reinforces the utility of multi-omics profiling as a methodology to understand human disease.

scholarly journals The Prognostic Impact of Protein Expression of E-Cadherin-Catenin Complexes Differs between Rectal and Colon Carcinoma

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Rolf Aamodt ◽  
Johan Bondi ◽  
Solveig Norheim Andersen ◽  
Arne Bakka ◽  
Geir Bukholm ◽  
...  
Keyword(s):  
Protein Expression ◽  
Clinical Information ◽  
Distant Metastases ◽  
Prognostic Impact ◽  
Inverse Association ◽  
Expression Data ◽  
P120 Catenin ◽  
Primary Tumors ◽  
Membranous Protein ◽  
E Cadherin

The E-cadherin-catenin complex provides cell-cell adhesion. In order for a carcinoma to metastasize, cancer cells must let go of their hold of neighboring cells in the primary tumor. The presence of components of the E-cadherin-catenin complex in 246 rectal adenocarcinomas was examined by immunohistochemistry and compared to their presence in 219 colon carcinomas. The expression data were correlated to clinical information from the patients' records. There were statistically significant differences in protein expression between the rectal and the colon carcinomas regarding membranous -catenin, -catenin, p120-catenin, and E-cadherin, as well as nuclear -catenin. In the rectal carcinomas, there was a significant inverse association between the expression of p120-catenin in cell membranes of the primary tumors and the occurrence of local recurrence, while membranous protein expression of -catenin was inversely related to distant metastases.

scholarly journals Non-Coding RNAs as Biomarkers of Tumor Progression and Metastatic Spread in Epithelial Ovarian Cancer

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1839
Author(s):  
Karolina Seborova ◽  
Radka Vaclavikova ◽  
Lukas Rob ◽  
Pavel Soucek ◽  
Pavel Vodicka
Keyword(s):  
Ovarian Cancer ◽  
Tumor Progression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Distant Metastases ◽  
Regulatory Elements ◽  
Metastatic Spread ◽  
Response To Treatment ◽  
Primary Tumors ◽  
Non Coding Rnas

Ovarian cancer is one of the most common causes of death among gynecological malignancies. Molecular changes occurring in the primary tumor lead to metastatic spread into the peritoneum and the formation of distant metastases. Identification of these changes helps to reveal the nature of metastases development and decipher early biomarkers of prognosis and disease progression. Comparing differences in gene expression profiles between primary tumors and metastases, together with disclosing their epigenetic regulation, provides interesting associations with progression and metastasizing. Regulatory elements from the non-coding RNA families such as microRNAs and long non-coding RNAs seem to participate in these processes and represent potential molecular biomarkers of patient prognosis. Progress in therapy individualization and its proper targeting also rely upon a better understanding of interactions among the above-listed factors. This review aims to summarize currently available findings of microRNAs and long non-coding RNAs linked with tumor progression and metastatic process in ovarian cancer. These biomolecules provide promising tools for monitoring the patient’s response to treatment, and further they serve as potential therapeutic targets of this deadly disease.

scholarly journals Improved risk estimation of locoregional recurrence, secondary contralateral tumors and distant metastases in early breast cancer: the INFLUENCE 2.0 model

2021 ◽  
Author(s):  
Vinzenz Völkel ◽  
Tom A. Hueting ◽  
Teresa Draeger ◽  
Marissa C. van Maaren ◽  
Linda de Munck ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Locoregional Recurrence ◽  
Clinical Decision Making ◽  
Metastatic Breast ◽  
Distant Metastases ◽  
Time Dependent ◽  
Individual Risk ◽  
Primary Tumors ◽  
Statistical Approaches

Abstract Purpose To extend the functionality of the existing INFLUENCE nomogram for locoregional recurrence (LRR) of breast cancer toward the prediction of secondary primary tumors (SP) and distant metastases (DM) using updated follow-up data and the best suitable statistical approaches. Methods Data on women diagnosed with non-metastatic invasive breast cancer were derived from the Netherlands Cancer Registry (n = 13,494). To provide flexible time-dependent individual risk predictions for LRR, SP, and DM, three statistical approaches were assessed; a Cox proportional hazard approach (COX), a parametric spline approach (PAR), and a random survival forest (RSF). These approaches were evaluated on their discrimination using the Area Under the Curve (AUC) statistic and on calibration using the Integrated Calibration Index (ICI). To correct for optimism, the performance measures were assessed by drawing 200 bootstrap samples. Results Age, tumor grade, pT, pN, multifocality, type of surgery, hormonal receptor status, HER2-status, and adjuvant therapy were included as predictors. While all three approaches showed adequate calibration, the RSF approach offers the best optimism-corrected 5-year AUC for LRR (0.75, 95%CI: 0.74–0.76) and SP (0.67, 95%CI: 0.65–0.68). For the prediction of DM, all three approaches showed equivalent discrimination (5-year AUC: 0.77–0.78), while COX seems to have an advantage concerning calibration (ICI < 0.01). Finally, an online calculator of INFLUENCE 2.0 was created. Conclusions INFLUENCE 2.0 is a flexible model to predict time-dependent individual risks of LRR, SP and DM at a 5-year scale; it can support clinical decision-making regarding personalized follow-up strategies for curatively treated non-metastatic breast cancer patients.

scholarly journals Regulatory T lymphocyte infiltration in metastatic breast cancer—an independent prognostic factor that changes with tumor progression

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Jenny Stenström ◽  
Ingrid Hedenfalk ◽  
Catharina Hagerling
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Lymph Node ◽  
Prognostic Factor ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Metastatic Breast ◽  
Distant Metastases ◽  
Independent Prognostic Factor ◽  
Primary Tumors

Abstract Background Patients diagnosed with metastatic breast cancer have poor outcome with a median survival of approximately 2 years. While novel therapeutic options are urgently needed, the great majority of breast cancer research has focused on the primary tumor and less is known about metastatic breast cancer and the prognostic impact of the metastatic tumor microenvironment. Here we investigate the immune landscape in unique clinical material. We explore how the immune landscape changes with metastatic progression and elucidate the prognostic role of immune cells infiltrating primary tumors and corresponding lymph node and more importantly distant metastases. Methods Immunohistochemical staining was performed on human breast cancer tissue microarrays from primary tumors (n = 231), lymph node metastases (n = 129), and distant metastases (n = 43). Infiltration levels of T lymphocytes (CD3+), regulatory T lymphocytes (Tregs, FOXP3+), macrophages (CD68+), and neutrophils (NE+) were assessed in primary tumors. T lymphocytes and Tregs were further investigated in lymph node and distant metastases. Results T lymphocyte and Treg infiltration were the most clinically important immune cell populations in primary tumors. Infiltration of T lymphocytes and Tregs in primary tumors correlated with proliferation (P = 0.007, P = 0.000) and estrogen receptor negativity (P = 0.046, P = 0.026). While both T lymphocyte and Treg infiltration had a negative correlation to luminal A subtype (P = 0.031, P = 0.000), only Treg infiltration correlated to luminal B (P = 0.034) and triple-negative subtype (P = 0.019). In primary tumors, infiltration of T lymphocytes was an independent prognostic factor for recurrence-free survival (HR = 1.77, CI = 1.01–3.13, P = 0.048), while Treg infiltration was an independent prognostic factor for breast cancer-specific survival (HR = 1.72, CI = 1.14–2.59, P = 0.01). Moreover, breast cancer patients with Treg infiltration in their distant metastases had poor post-recurrence survival (P = 0.039). Treg infiltration levels changed with metastatic tumor progression in 50% of the patients, but there was no significant trend toward neither lower nor higher infiltration. Conclusion Treg infiltration could have clinical applicability as a prognostic biomarker, deciphering metastatic breast cancer patients with worse prognosis, and accordingly, could be a suitable immunotherapeutic target for patients with metastatic breast cancer. Importantly, half of the patients had changes in Treg infiltration during the course of metastatic progression emphasizing the need to characterize the metastatic immune landscape.

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