| 1. |
- Blom, Anna M, et al.
(författare)
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Expression of Cartilage Oligomeric Matrix Protein in colorectal cancer is an adverse prognostic factor and correlates negatively with infiltrating immune cells and PD-L1 expression
- 2023
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Ingår i: Frontiers in Immunology. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Cartilage Oligomeric Matrix Protein (COMP) is an oncogenic protein that has been associated with a decrease in infiltrating T-cells in periampullary adenocarcinoma. This study aimed to investigate whether this is also the case for colorectal cancer (CRC) and to evaluate the relationship between COMP expression and clinopathological features.METHODS: Immunohistochemistry was used to determine the expression levels of COMP in tumor cells and stroma in primary tumors from a cohort of 537 CRC patients. The expression of immune cell markers, including CD3+, CD8+, FoxP3+, CD68+, CD56+, CD163+, and PD-L1, was evaluated previously. Tumor fibrosis was assessed by Sirius Red staining and evaluation of collagen fiber organization.RESULTS: COMP expression correlated positively with TNM-stage and grade of differentiation. Patients with CRC expressing high levels of COMP had significantly shorter OS than those with low COMP expression (p<0.0001), and fewer infiltrating T-cells were detected in tumors with high COMP expression. Additionally, a negative correlation was identified between the expression of COMP and PD-L1 on both tumor cells and immune cells. Cox regression analysis showed that tumors expressing high levels of COMP had significantly shorter OS, independent of all evaluated immune cell markers. Tumor fibrosis was correlated with high expression of COMP in the stroma (p<0.0001), and tumors with high levels of COMP expression and denser fibrosis displayed more sparse immune cell infiltration.DISCUSSION: The results suggest that COMP expression in CRC may exert an immune regulatory effect by increasing dense fibrosis and decreasing immune cell infiltration. These findings support the notion that COMP is an important factor in the development and progression of CRC.
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| 2. |
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| 3. |
- Englund, Emelie, et al.
(författare)
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Cartilage oligomeric matrix protein promotes prostate cancer progression by enhancing invasion and disrupting intracellular calcium homeostasis
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:58, s. 98298-98311
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Tidskriftsartikel (refereegranskat)abstract
- Cartilage oligomeric matrix protein (COMP) was recently implicated in the progression of breast cancer. Immunostaining of 342 prostate cancer specimens in tissue microarrays showed that COMP expression is not breast cancer-specific but also occurs in prostate cancer. The expression of COMP in prostate cancer cells correlated with a more aggressive disease with faster recurrence. Subcutaneous xenografts in immunodeficient mice showed that the prostate cancer cell line DU145 overexpressing COMP formed larger tumors in vivo as compared to mock-transfected cells. Purified COMP bound to and enhanced the invasion of DU145 cells in vitro in an integrin-dependent manner. In addition, intracellular COMP expression interfered with cellular metabolism by causing a decreased level of oxidative phosphorylation with a concurrent upregulation of lactate production (Warburg effect). Further, expression of COMP protected cells from induction of apoptosis via several pathways. The effect of COMP on metabolism and apoptosis induction was dependent on the ability of COMP to disrupt intracellular Ca2+ signalling by preventing Ca2+ release from the endoplasmic reticulum. In conclusion, COMP is a potent driver of the progression of prostate cancer, acting in an anti-apoptotic fashion by interfering with the Ca2+ homeostasis of cancer cells.
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| 4. |
- Gialeli, Chrysostomi, et al.
(författare)
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Complement inhibitor CSMD1 modulates epidermal growth factor receptor oncogenic signaling and sensitizes breast cancer cells to chemotherapy
- 2021
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Ingår i: Journal of Experimental and Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966. ; 40:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Human CUB and Sushi multiple domains 1 (CSMD1) is a large membrane-bound tumor suppressor in breast cancer. The current study aimed to elucidate the molecular mechanism underlying the effect of CSMD1 in highly invasive triple negative breast cancer (TNBC). Methods: We examined the antitumor action of CSMD1 in three TNBC cell lines overexpressing CSMD1, MDA-MB-231, BT-20 and MDA-MB-486, in vitro using scanning electron microscopy, proteome array, qRT-PCR, immunoblotting, proximity ligation assay, ELISA, co-immunoprecipitation, immunofluorescence, tumorsphere formation assays and flow cytometric analysis. The mRNA expression pattern and clinical relevance of CSMD1 were evaluated in 3520 breast cancers from a modern population-based cohort. Results: CSMD1-expressing cells had distinct morphology, with reduced deposition of extracellular matrix components. We found altered expression of several cancer-related molecules, as well as diminished expression of signaling receptors including Epidermal Growth Factor Receptor (EGFR), in CSMD1-expressing cells compared to control cells. A direct interaction of CSMD1 and EGFR was identified, with the EGF-EGFR induced signaling cascade impeded in the presence of CSMD1. Accordingly, we detected increased ubiquitination levels of EGFR upon activation in CSMD1-expressing cells, as well as increased degradation kinetics and chemosensitivity. Accordingly, CSMD1 expression rendered tumorspheres pretreated with gefitinib more sensitive to chemotherapy. In addition, higher mRNA levels of CSMD1 tend to be associated with better outcome of triple negative breast cancer patients treated with chemotherapy. Conclusions: Our results indicate that CSMD1 cross-talks with the EGFR endosomal trafficking cascade in a way that renders highly invasive breast cancer cells sensitive to chemotherapy. Our study unravels one possible underlying molecular mechanism of CSMD1 tumor suppressor function and may provide novel avenues for design of better treatment.
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| 5. |
- Papadakos, Konstantinos S., et al.
(författare)
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Cartilage Oligomeric Matrix Protein initiates cancer stem cells through activation of Jagged1-Notch3 signaling
- 2019
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Ingår i: Matrix Biology. - : Elsevier BV. - 0945-053X. ; 81, s. 107-121
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Tidskriftsartikel (refereegranskat)abstract
- Cancer stem cell populations are important for the initiation, progression and metastasis of tumors. The mechanisms governing cancer stem cell control are only partially understood, but activation of the Notch3 pathway plays a crucial role in the maintenance of breast cancer stem cells. Expression of Cartilage Oligomeric Matrix Protein (COMP) in breast cancer cells is correlated with poor survival and higher recurrence rates in patients. In this study, we provide in vivo and in vitro evidence that COMP expression increases the proportion of cancer stem cells in breast cancer. Thus, MDA-MB-231 and BT-20 cells expressing COMP formed larger tumorspheres in vivo and in vitro and displayed higher ALDH-activity than cells lacking COMP. Additionally, BT-20 COMP-expressing cells displayed higher expression of CD133 compared with the control cells. Furthermore, among the different Notch receptors, Notch3 is specifically activated in COMP-expressing cells. Mechanistically, activation of Notch3 is mediated by secreted, polymeric COMP, which interacts with both Notch3 and its ligand Jagged1, bridging the receptor and ligand together, enhancing Notch3-specific signaling. COMP-dependent Notch3 activation also leads to cross-talk with β-Catenin and AKT pathways. Using the model of MMTV-PyMT mouse breast tumorigenesis, we observed a decrease in the size of tumors and the amount of cancer stem cells as well as reduced Notch3 activation, in COMP knockout mice in comparison to wild type mice. In conclusion, we reveal a novel molecular mechanism whereby COMP regulates the cancer stem cell population through increasing the interaction between Notch3 and Jagged1, leading to increased activation of Notch3 signaling.
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| 6. |
- Papadakos, Konstantinos S., et al.
(författare)
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Expression of cartilage oligomeric matrix protein in periampullary adenocarcinoma is associated with pancreatobiliary-type morphology, higher levels of fibrosis and immune cell exclusion
- 2022
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Ingår i: Oncoimmunology. - : Taylor & Francis. - 2162-4011 .- 2162-402X. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Cartilage oligomeric matrix protein (COMP) is an emerging regulator of tumor progression. The aim of this study was to evaluate the expression of COMP in periampullary adenocarcinoma with respect to prognostic value for survival and relapse, levels of fibrosis and infiltrating immune cells. COMP expression was evaluated using immunohistochemistry in primary tumors and subsets of paired lymph node metastases in tissue microarrays including 175 patients with periampullary adenocarcinoma. Collagen content was assessed with Sirius Red-Fast Green staining. High COMP levels were detected in cancer cells and in stroma, in 46% and 57% of the patients, respectively. High COMP expression was strongly associated with more aggressive pancreatobiliary-type (PB-type) compared to intestinal-type tumors (p < .0001). Importantly, high expression of COMP correlated with the exclusion of cytotoxic T-cells from the cancer cell compartment of the tumors, particularly in PB-type tumors. Higher levels of fibrosis measured by the density of collagen fibers correlated with high COMP levels in both cancer cells and stroma. This in turn could lead to exclusion of cytotoxic T-cells from accessing the cancer cells, a recognized immunotherapy resistance mechanism. Targeting COMP could therefore be considered as a novel therapeutic strategy in PB-type periampullary adenocarcinoma.
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| 7. |
- Papadakos, Konstantinos S., et al.
(författare)
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High levels of cartilage oligomeric matrix protein in the serum of breast cancer patients can serve as an independent prognostic marker
- 2019
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 9:OCT
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cartilage oligomeric matrix protein (COMP) is a pentameric cartilage protein also expressed in breast cancer tumors. A high expression of COMP evaluated by immunohistochemical staining is as an independent prognostic marker associated with poor patients’ prognosis. Methods: Herein, levels of COMP were analyzed using an IVD approved ELISA in serum samples from 233 well-characterized breast cancer patients; 176 with metastatic breast cancer; and 57 in an early stage of the disease. Results: The metastatic patients had double the concentration of serum COMP compared with those with early breast cancer. High levels of COMP in sera of metastatic patients were associated with the histological subtype (p = 0.025) and estrogen receptor positivity (p = 0.019) at the time of breast cancer diagnosis. Further, correlation was observed between the serum levels of COMP and the presence of liver (p = 0.010) or bone (p = 0.010) metastases in this population. Most importantly, elevated serum levels of COMP appear to serve as an independent prognostic marker of survival as assessed by Cox proportional hazard regression analysis (p = 0.001) for the metastatic patients. Among metastatic patients treated with taxanes (Docetaxel-Paclitaxel) as part of their first metastatic line (n = 25), those with high levels of serum COMP detected in the metastatic stage of the disease had a shorter median survival (0.2 years) compared with those with low levels of serum COMP (1.1 years) (p = 0.001). Conclusions: Taken together, the serum levels of COMP are elevated in the metastatic patients and may be a potential novel biomarker for the evaluation of the prognosis in this population.
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| 8. |
- Papadakos, Konstantinos S., et al.
(författare)
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High levels of expression of cartilage oligomeric matrix protein in lymph node metastases in breast cancer are associated with reduced survival
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:23
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Tidskriftsartikel (refereegranskat)abstract
- Cartilage oligomeric matrix protein (COMP) is a regulator of the extracellular matrix and is expressed primarily in the cartilage. Recently, COMP expression was also documented in breast cancer patients both in sera and tumor biopsies, in both of which it could serve as an independent prognostic marker. This study aimed to assess COMP as a potential biomarker in the group of metastatic breast cancer patients. Levels of COMP were measured by ELISA in serum samples of 141 metastatic breast cancer patients. Biopsies from primary tumors, synchronous lymph node metastases, and distant metastases were stained for COMP expression. The levels of serum COMP were higher in patients with ER‐ and HER2‐positive tumors when compared to triple‐negative tumors and correlated with the presence of bone and lung metastases, circulating tumor cell count, and clusters. Most of the primary tumors expressing COMP (70%) retained the expression also in the lymph node metastases, which correlated with visceral metastases and reduced survival. In conclusion, COMP appears as a valuable biomarker in metastatic breast cancer patients indicating a more severe stage of the disease. Serum COMP levels were associated with specific types of metastases in patients with metastatic breast cancer emphasizing that further studies are warranted to elucidate its potential role as a monitoring marker.
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| 9. |
- Papadakos, Konstantinos S, et al.
(författare)
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Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent manner
- 2022
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Ingår i: Journal of Experimental and Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966. ; 41:1, s. 363-363
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sushi domain-containing protein 4 (SUSD4) is a recently discovered protein with unknown cellular functions. We previously revealed that SUSD4 can act as complement inhibitor and as a potential tumor suppressor.METHODS: In a syngeneic mouse model of breast cancer, tumors expressing SUSD4 had a smaller volume compared with the corresponding mock control tumors. Additionally, data from three different expression databases and online analysis tools confirm that for breast cancer patients, high mRNA expression of SUSD4 in the tumor tissue correlates with a better prognosis. In vitro experiments utilized triple-negative breast cancer cell lines (BT-20 and MDA-MB-468) stably expressing SUSD4. Moreover, we established a cell line based on BT-20 in which the gene for EGFR was knocked out with the CRISPR-Cas9 method.RESULTS: We discovered that the Epithelial Growth Factor Receptor (EGFR) interacts with SUSD4. Furthermore, triple-negative breast cancer cell lines stably expressing SUSD4 had higher autophagic flux. The initiation of autophagy required the expression of EGFR but not phosphorylation of the receptor. Expression of SUSD4 in the breast cancer cells led to activation of the tumor suppressor LKB1 and consequently to the activation of AMPKα1. Finally, autophagy was initiated after stimulation of the ULK1, Atg14 and Beclin-1 axis in SUSD4 expressing cells.CONCLUSIONS: In this study we provide novel insight into the molecular mechanism of action whereby SUSD4 acts as an EGFR inhibitor without affecting the phosphorylation of the receptor and may potentially influence the recycling of EGFR to the plasma membrane.
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| 10. |
- Papadakos, Konstantinos S, et al.
(författare)
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The prognostic and potentially immunomodulatory role of cartilage oligomeric matrix protein in patients with gastric and esophageal adenocarcinoma
- 2024
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Ingår i: Cancer Immunology Immunotherapy. - 1432-0851. ; 73:5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cartilage oligomeric matrix protein (COMP) is a novel regulator of the tumor microenvironment. Studies in colon cancer and pancreatobiliary adenocarcinoma have revealed COMP expression to be associated with decreased infiltration of immune cells in the tumor microenvironment. Herein, the expression of COMP was investigated in gastric and esophageal adenocarcinoma with particular reference to its the relationship with the immune microenvironment.METHODS: COMP expression was evaluated in tissue microarrays representing primary tumors from 159 patients with chemo- and radiotherapy naïve esophageal and gastric adenocarcinoma and 67 matched samples of lymph node metastases using immunohistochemistry. Additionally, collagen fibers were stained with Sirius Red and evaluated with the FIJI macro TWOMBLI algorithm.RESULTS: The expression of COMP in cancer cells in the entire cohort was associated with shorter overall survival (OS) (p = 0.013) and recurrence-free survival (RFS) (p = 0.029), while COMP expression in the stroma was correlated with shorter RFS (p = 0.042). Similar correlations were found for patients with gastric adenocarcinoma, whereas COMP expression was not prognostic in esophageal adenocarcinoma. Further, in the entire cohort, the expression of COMP in the stroma was correlated with exclusion of different populations of immune cells (CD8+, CD3+, FoxP3+, CD20+) from the tumor microenvironment. Finally, higher density and alignment of collagen fibers were correlated with the expression of COMP in the stroma.CONCLUSIONS: Expression of COMP in gastric and esophageal adenocarcinoma was correlated with shorter OS and RFS. A reduced number of immune cells infiltrated the tumor microenvironment when COMP expression was detected. This phenomenon could be attributed to the denser collagen deposits, a hallmark of tumor fibrosis observed in COMP-expressing tumors.
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