scholarly journals TIMP-2 secreted by monocyte-like cells is a potent suppressor of invadopodia formation in pancreatic cancer cells

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Christian Benzing ◽  
Hoyin Lam ◽  
Chi Man Tsang ◽  
Alexander Rimmer ◽  
Yoana Arroyo-Berdugo ◽  
...  
Keyword(s):  
Tumor Invasion ◽  
Primary Tumour ◽  
Tumour Microenvironment ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Ductal Adenocarcinoma ◽  
Complex Interactions ◽  
Pancreatic Cancer Cells ◽  
Therapeutic Opportunity ◽  
The Impact ◽  
Invadopodia Formation

Abstract Background Monocytes are a major component of the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC). However, the complex interactions between tumor cells and monocytes and their role in tumor invasion have not been fully established. Methods To specifically test the impact of interaction on invasive potential two PDAC cell lines PaTu8902 and CFPAC-1 were selected on their ability to form invasive adhesions, otherwise known as invadopodia and invade in a spheroid invasion assay. Results Interestingly when the PDAC cells were co-cultured with undifferentiated THP1 monocyte-like cells invadopodia formation was significantly suppressed. Moreover, conditioned media of THP1 cells (CM) was also able to suppress invadopodia formation. Further investigation revealed that both tissue inhibitor of metalloproteinase (TIMP) 1 and 2 were present in the CM. However, suppression of invadopodia formation was found that was specific to TIMP2 activity. Conclusions Our findings indicate that TIMP2 levels in the tumour microenvironment may have prognostic value in patients with PDAC. Furthermore, activation of TIMP2 expressing monocytes in the primary tumour could present a potential therapeutic opportunity to suppress cell invasion in PDAC.

scholarly journals TIMP-2 secreted by monocyte-like cells is a potent suppressor of invadopodia formation in pancreatic cancer cells

2019 ◽  
Author(s):  
Christian Benzing ◽  
Hoyin Lam ◽  
Chi Man Tsang ◽  
Alexander Rimmer ◽  
Yoana Arroyo-Berdugo ◽  
...  
Keyword(s):  
Tumor Invasion ◽  
Primary Tumour ◽  
Tumour Microenvironment ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Ductal Adenocarcinoma ◽  
Complex Interactions ◽  
Pancreatic Cancer Cells ◽  
Therapeutic Opportunity ◽  
The Impact ◽  
Invadopodia Formation

Abstract Background Monocytes are a major component of the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC). However, the complex interactions between tumor cells and monocytes and their role in tumor invasion have not been fully established. Methods To specifically test the impact of interaction on invasive potential two PDAC cell lines PaTu8902 and CFPAC-1 were selected on their ability to form invasive adhesions, otherwise known as invadopodia and invade in a spheroid invasion assay. Results Interestingly when the PDAC cells were co-cultured with undifferentiated THP1 monocyte-like cells invadopodia formation was significantly suppressed. Moreover, conditioned media of THP1 cells (CM) was also able to suppress invadopodia formation. Further investigation revealed that both tissue inhibitor of metalloproteinase (TIMP) 1 and 2 were present in the CM. However, suppression of invadopodia formation was found that was specific to TIMP2 activity. Conclusions Our findings indicate that TIMP2 levels in the tumour microenvironment may have prognostic value in patients with PDAC. Furthermore, activation of TIMP2 expressing monocytes in the primary tumour could present a potential therapeutic opportunity to suppress cell invasion in PDAC

scholarly journals TIMP-2 secreted by monocytes-like cells is a potent suppressor of invadopodia formation in pancreatic cancer cells

2019 ◽  
Author(s):  
Christian Benzing ◽  
Hoyin Lam ◽  
Chi Man Tsang ◽  
Alexander Rimmer ◽  
Yoana Arroyo-Berdugo ◽  
...  
Keyword(s):  
Tumor Invasion ◽  
Primary Tumour ◽  
Tumour Microenvironment ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Ductal Adenocarcinoma ◽  
Complex Interactions ◽  
Pancreatic Cancer Cells ◽  
Therapeutic Opportunity ◽  
The Impact ◽  
Invadopodia Formation

Abstract Background Monocytes are a major component of the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC). However, the complex interactions between tumor cells and monocytes and their role in tumor invasion have not been fully established. Methods To specifically test the impact of interaction on invasive potential two PDAC cell lines PaTu8902 and CFPAC-1 were selected on their ability to form invasive adhesions, otherwise known as invadopodia and invade in a spheroid invasion assay. Results Interestingly when the PDAC cells were co-cultured with undifferentiated THP1 monocyte-like cells invadopodia formation was significantly suppressed. Moreover, conditioned media of THP1 cells (CM) was also able to suppress invadopodia formation. Further investigation revealed that both tissue inhibitor of metalloproteinase (TIMP) 1 and 2 were present in the CM. However, suppression of invadopodia formation was found that was specific to TIMP2 activity. Conclusions Our findings indicate that TIMP2 levels in the tumour microenvironment may have prognostic value in patients with PDAC. Furthermore, activation of TIMP2 expressing monocytes in the primary tumour could present a potential therapeutic opportunity to suppress cell invasion in PDAC

scholarly journals TIMP-2 secreted by monocytes is a potent suppressor of invadopodia formation in pancreatic cancer cells

2019 ◽  
Author(s):  
Christian Benzing ◽  
Hoyin Lam ◽  
Chi Man Tsang ◽  
Yoana Arroyo-Berdugo ◽  
Yolanda Calle-Patino ◽  
...  
Keyword(s):  
Primary Tumour ◽  
In Vitro Study ◽  
Tumour Microenvironment ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Therapeutic Opportunity ◽  
The Impact ◽  
Invadopodia Formation

Abstract Background Monocytes are a major component of the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC). However, the complex interactions between tumor cells and monocytes and their role in tumor invasion have not been fully established. Methods In this in vitro study, to specifically test the impact of interaction on invasive potential, two PDAC cell lines PaTu8902 and CFPAC-1 were selected on their ability to form invasive adhesions, otherwise known as invadopodia. Co-culture experiments were performed using undifferentiated THP1 monocytes. Results When the PDAC cells were co-cultured with undifferentiated THP1 monocytes invadopodia formation was significantly suppressed. Moreover, conditioned media of THP1 cells (CM) was also able to suppress invadopodia formation. Further investigation revealed that both tissue inhibitor of metalloproteinase (TIMP) 1 and 2 were present in the CM. However, suppression of invadopodia formation was found that was specific to TIMP2 activity. Conclusions Our findings indicate that TIMP2 levels in the tumour microenvironment may have prognostic value in patients with PDAC. Furthermore, activation of TIMP2 expressing monocytes in the primary tumour could present a potential therapeutic opportunity to suppress cell invasion in PDAC.

scholarly journals TIMP-2 secreted by monocytes is a potent suppressor of invadopodia formation in pancreatic cancer cells

2019 ◽  
Author(s):  
Christian Benzing ◽  
Hoyin Lam ◽  
Chi Man Tsang ◽  
Alexander Rimmer ◽  
Yoana Arroyo-Berdugo ◽  
...  
Keyword(s):  
Primary Tumour ◽  
In Vitro Study ◽  
Tumour Microenvironment ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Therapeutic Opportunity ◽  
The Impact ◽  
Invadopodia Formation

Abstract Background Monocytes are a major component of the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC). However, the complex interactions between tumor cells and monocytes and their role in tumor invasion have not been fully established. Methods In this in vitro study, to specifically test the impact of interaction on invasive potential, two PDAC cell lines PaTu8902 and CFPAC-1 were selected on their ability to form invasive adhesions, otherwise known as invadopodia. Co-culture experiments were performed using undifferentiated THP1 monocytes. Results When the PDAC cells were co-cultured with undifferentiated THP1 monocytes invadopodia formation was significantly suppressed. Moreover, conditioned media of THP1 cells (CM) was also able to suppress invadopodia formation. Further investigation revealed that both tissue inhibitor of metalloproteinase (TIMP) 1 and 2 were present in the CM. However, suppression of invadopodia formation was found that was specific to TIMP2 activity. Conclusions Our findings indicate that TIMP2 levels in the tumour microenvironment may have prognostic value in patients with PDAC. Furthermore, activation of TIMP2 expressing monocytes in the primary tumour could present a potential therapeutic opportunity to suppress cell invasion in PDAC.

scholarly journals Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer

Gut ◽  
2018 ◽  
Vol 68 (4) ◽  
pp. 693-707 ◽  
Author(s):  
Delphine Goehrig ◽  
Jérémy Nigri ◽  
Rémi Samain ◽  
Zhichong Wu ◽  
Paola Cappello ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumour Growth ◽  
Matrix Protein ◽  
Immune Escape ◽  
Interaction Mechanism ◽  
Tumour Microenvironment ◽  
Extracellular Matrix Protein ◽  
Ductal Adenocarcinoma ◽  
The Impact

ObjectivePancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of βig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer.DesignWe performed studies with p48-Cre;KrasG12D, pdx1-Cre;KrasG12D;Ink4a/Arffl/fl, pdx1-Cre;KrasG12D; p53R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-βig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy.ResultsWe identified βig-h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that βig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8+ T cells and F4/80 macrophages. Depleting βig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8+ T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting βig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment.ConclusionsOur data indicate that targeting stromal extracellular matrix protein βig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present βig-h3 as a novel immunological target in pancreatic cancer.

scholarly journals Aspartate β-hydroxylase promotes pancreatic ductal adenocarcinoma metastasis through activation of SRC signaling pathway

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Kosuke Ogawa ◽  
Qiushi Lin ◽  
Le Li ◽  
Xuewei Bai ◽  
Xuesong Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Stem Cell Marker ◽  
Ductal Adenocarcinoma ◽  
Physical Interaction ◽  
Pancreatic Cancer Cells ◽  
Ecm Degradation ◽  
Invadopodia Formation ◽  
Pdx Models

Abstract Background Signaling pathways critical for embryonic development re-emerge in adult pancreas during tumorigenesis. Aspartate β-hydroxylase (ASPH) drives embryonic cell motility/invasion in pancreatic development/differentiation. We explored if dysregulated ASPH is critically involved in pancreatic cancer pathogenesis. Methods To demonstrate if/how ASPH mediates malignant phenotypes, proliferation, migration, 2-D/3-D invasion, pancreatosphere formation, immunofluorescence, Western blot, co-immunoprecipitation, invadopodia formation/maturation/function, qRT-PCR, immunohistochemistry (IHC), and self-developed in vitro metastasis assays were performed. Patient-derived xenograft (PDX) models of human pancreatic ductal adenocarcinoma (PDAC) were established to illustrate in vivo antitumor effects of the third-generation small molecule inhibitor specifically against ASPH’s β-hydroxylase activity. Prognostic values of ASPH network components were evaluated with Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models. Results ASPH renders pancreatic cancer cells more aggressive phenotypes characterized by epithelial–mesenchymal transition (EMT), 2-D/3-D invasion, invadopodia formation/function as demonstrated by extracellular matrix (ECM) degradation, stemness (cancer stem cell marker upregulation and pancreatosphere formation), transendothelial migration (mimicking intravasation/extravasation), and sphere formation (mimicking metastatic colonization/outgrowth at distant sites). Mechanistically, ASPH activates SRC cascade through direct physical interaction with ADAM12/ADAM15 independent of FAK. The ASPH-SRC axis enables invadopodia construction and initiates MMP-mediated ECM degradation/remodeling as executors for invasiveness. Pharmacologic inhibition of invadopodia attenuates in vitro metastasis. ASPH fosters primary tumor development and pulmonary metastasis in PDX models of PDAC, which is blocked by a leading compound specifically against ASPH enzymatic activity. ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stages of PDAC. Expression profiling of ASPH-SRC network components independently/jointly predicts clinical outcome of PDAC patients. Compared to a negative-low level, a moderate-very high level of ASPH, ADAM12, activated SRC, and MMPs correlated with curtailed overall survival (OS) of pancreatic cancer patients (log-rank test, ps < 0.001). The more unfavorable molecules patients carry, the more deleterious prognosis is destinated. Patients with 0–2 (n = 4), 3–5 (n = 8), 6–8 (n = 24), and 9–12 (n = 73) unfavorable expression scores of the 5 molecules had median survival time of 55.4, 15.9, 9.7, and 5.0 months, respectively (p < 0.001). Conclusion Targeting the ASPH-SRC axis, which is essential for propagating multi-step PDAC metastasis, may specifically/substantially retard development/progression and thus improve prognosis of PDAC.

scholarly journals Kallikrein-Related Peptidase 6 Is Associated with the Tumour Microenvironment of Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3969
Author(s):  
Juliana B. Candido ◽  
Oscar Maiques ◽  
Melanie Boxberg ◽  
Verena Kast ◽  
Eleonora Peerani ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Standard Of Care ◽  
Tumour Microenvironment ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Approaches ◽  
Novel Treatments ◽  
Pancreatic Cancer Cells ◽  
Invasive Tumour ◽  
Mrna And Protein Expression

As cancer-associated factors, kallikrein-related peptidases (KLKs) are components of the tumour microenvironment, which represents a rich substrate repertoire, and considered attractive targets for the development of novel treatments. Standard-of-care therapy of pancreatic cancer shows unsatisfactory results, indicating the need for alternative therapeutic approaches. We aimed to investigate the expression of KLKs in pancreatic cancer and to inhibit the function of KLK6 in pancreatic cancer cells. KLK6, KLK7, KLK8, KLK10 and KLK11 were coexpressed and upregulated in tissues from pancreatic cancer patients compared to normal pancreas. Their high expression levels correlated with each other and were linked to shorter survival compared to low KLK levels. We then validated KLK6 mRNA and protein expression in patient-derived tissues and pancreatic cancer cells. Coexpression of KLK6 with KRT19, αSMA or CD68 was independent of tumour stage, while KLK6 was coexpressed with KRT19 and CD68 in the invasive tumour area. High KLK6 levels in tumour and CD68+ cells were linked to shorter survival. KLK6 inhibition reduced KLK6 mRNA expression, cell metabolic activity and KLK6 secretion and increased the secretion of other serine and aspartic lysosomal proteases. The association of high KLK levels and poor prognosis suggests that inhibiting KLKs may be a therapeutic strategy for precision medicine.

scholarly journals Role of Microenvironment in Ovarian Tumourisation

2021 ◽  
Vol 11 (4) ◽  
pp. 278-283
Author(s):  
L. V. Khalikova ◽  
N. N. Shevlyuk ◽  
Sh. Kh. Gantsev ◽  
A. A. Khalikov ◽  
I. R. Khasanova
Keyword(s):  
Disease Progression ◽  
Primary Tumour ◽  
Tumour Microenvironment ◽  
Greater Omentum ◽  
Malignant Neoplasms ◽  
Tissue Samples ◽  
Advanced Malignancy ◽  
Cell Counts ◽  
Multistep Process ◽  
The Impact

Background. Metastasis is a formidable complication of malignant neoplasms, with therapy not always effective in advanced malignancy. Metastasis is a multistep process involving the cancer cell detachment from primary tumour, intravasation, extravasation and invasion into the target organ. Early metastasis stages are well understood, whilst the impact of tumour microenvironment on the disease progression and advancement remains a matter of debate.Aim. An immunohistochemical study of the adaptive and reactive properties of greater omentum with metastatic involvement in ovarian cancer.Materials and methods. We examined greater omentum tissue samples from 40 patients with verifi ed stage 3a and b ovarian cancers. For light microscopy, samples were fi xed in 10 % formalin, dehydrated, paraffi n-embedded and stained with Mayer’s haematoxylin and eosin. Immunohistochemical assays used monoclonal antibodies against CD7, CD4, CD8, CD 68, VEGF, D2-40 and CD44 proteins. Statistical data analysis was performed with Statistica v. 7.0 soft ware.Results and discussion. Analyses of the greater omentum tissues revealed cases of leucocyte-bank encapsulation of metastatic foci. Higher CD7+ and CD8+ cell counts were observed in encapsulation, possibly influencing the greater omentum reactive and adaptive properties. Higher CD44-expressing cell counts were also detected in greater omentum samples lacking encapsulation. Angiogenesis marker-expressing cells (e.g., VEGF and CD34) predominated in greater omentum tissues lacking leucocyte-bank encapsulation of metastatic foci.Conclusion. Events in tumour microenvironment may be indicative of a preserved or reduced organ adaptivity, the latter facilitating disease progression.

DNAJA1 dysregulates metabolism promoting an anti-apoptotic phenotype in pancreatic ductal adenocarcinoma

2020 ◽  
Author(s):  
Heidi Roth ◽  
Fatema Bhinderwala ◽  
Rodrigo Franco ◽  
You Zhou ◽  
Robert Powers
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
The Impact

Abstract BackgroundAt less than 7%, pancreatic ductal adenocarcinoma (PDAC) has one of the poorest 5-year cancer survival rates and is set to be the leading cause of cancer related deaths by 2030. The co-chaperone protein DNAJA1 (HSP40) is downregulated four-fold in pancreatic cancer cells, but its impact on pancreatic ductal adenocarcinoma (PDAC) progression remains unclear.MethodsDNAJA1 was overexpressed in pancreatic cancer cell lines, BxPC-3 and MIA PaCa-2, through retroviral transfection. The impact of overexpressing DNAJA1 was investigated using a combination of untargeted metabolomics, stable isotope resolved metabolomics (SIRM), confocal microscopy, flow-cytometry, and cell-based assays.ResultsPancreatic cancer cells overexpressing DNAJA1 exhibited a global metabolomic change. Specifically, differential output from Warburg glycolysis, an increase in redox currency, and an alteration in amino acid levels were observed in both overexpression cell lines. DNAJA1 overexpression also led to mitochondrial fusion, an increase in the expression of Bcl-2, a modest protection from redox induced cell death, a loss of structural integrity due to the loss of actin fibers, and an increase in cell invasiveness in BxPC-3. These differences were more pronounced in BxPC-3, which contains a loss-of-function mutation in the tumor suppressing gene SMAD4.ConclusionsThe overexpression of DNAJA1 promoted cellular proliferation, redox tolerance, invasiveness, and anti-apoptosis, which suggests DNAJA1 has numerous regulatory roles. Overall, our findings suggest a proto-oncogenic role of DNAJA1 in PDAC progression and suggests DNAJA1 may function synergistically with other proteins with altered activity in pancreatic cancer cell lines.

scholarly journals Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer

Gut ◽  
2017 ◽  
Vol 67 (3) ◽  
pp. 497-507 ◽  
Author(s):  
E Hessmann ◽  
M S Patzak ◽  
L Klein ◽  
N Chen ◽  
V Kari ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Liver Metastases ◽  
Recombinant Expression ◽  
Primary Tumour ◽  
Normal Liver ◽  
Tumour Microenvironment ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma

ObjectiveDesmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery.DesignGemcitabine metabolites were analysed in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) murine tumours and matched liver metastases, primary tumour cell lines, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) by liquid chromatography-mass spectrometry/mass spectrometry. Functional and preclinical experiments, as well as expression analysis of stromal markers and gemcitabine metabolism pathways were performed in murine and human specimen to investigate the preclinical implications and the mechanism of gemcitabine accumulation.ResultsGemcitabine accumulation was significantly enhanced in fibroblast-rich tumours compared with liver metastases and normal liver. In vitro, significantly increased concentrations of activated 2′,2′-difluorodeoxycytidine-5′-triphosphate (dFdCTP) and greatly reduced amounts of the inactive gemcitabine metabolite 2′,2′-difluorodeoxyuridine were detected in PSCs and CAFs. Mechanistically, key metabolic enzymes involved in gemcitabine inactivation such as hydrolytic cytosolic 5′-nucleotidases (Nt5c1A, Nt5c3) were expressed at low levels in CAFs in vitro and in vivo, and recombinant expression of Nt5c1A resulted in decreased intracellular dFdCTP concentrations in vitro. Moreover, gemcitabine treatment in KPC mice reduced the number of liver metastases by >50%.ConclusionsOur findings suggest that fibroblast drug scavenging may contribute to the clinical failure of gemcitabine in desmoplastic PDAC. Metabolic targeting of CAFs may thus be a promising strategy to enhance the antiproliferative effects of gemcitabine.

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