scholarly journals Clinical and Pre-Clinical Evidence of Carbonic Anhydrase IX in Pancreatic Cancer and Its High Expression in Pre-Cancerous Lesions

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2005 ◽  
Author(s):  
Sabina Strapcova ◽  
Martina Takacova ◽  
Lucia Csaderova ◽  
Paola Martinelli ◽  
Lubomira Lukacikova ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Carbonic Anhydrase ◽  
Cancer Patients ◽  
Carbonic Anhydrase Ix ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Pancreatic Cancers ◽  
Caix Expression ◽  
Cancerous Lesions ◽  
First Time

Hypoxia is a common phenomenon that occurs in most solid tumors. Regardless of tumor origin, the evolution of a hypoxia-adapted phenotype is critical for invasive cancer development. Pancreatic ductal adenocarcinoma is also characterized by hypoxia, desmoplasia, and the presence of necrosis, predicting poor outcome. Carbonic anhydrase IX (CAIX) is one of the most strict hypoxia regulated genes which plays a key role in the adaptation of cancer cells to hypoxia and acidosis. Here, we summarize clinical data showing that CAIX expression is associated with tumor necrosis, vascularization, expression of Frizzled-1, mucins, or proteins involved in glycolysis, and inevitably, poor prognosis of pancreatic cancer patients. We also describe the transcriptional regulation of CAIX in relation to signaling pathways activated in pancreatic cancers. A large part deals with the preclinical evidence supporting the relevance of CAIX in processes leading to the aggressive behavior of pancreatic tumors. Furthermore, we focus on CAIX occurrence in pre-cancerous lesions, and for the first time, we describe CAIX expression within intraductal papillary mucinous neoplasia. Our review concludes with a detailed account of clinical trials implicating that treatment consisting of conventionally used therapies combined with CAIX targeting could result in an improved anti-cancer response in pancreatic cancer patients.

scholarly journals Role of carbonic anhydrase IX expression in prediction of the efficacy and outcome of primary epirubicin/tamoxifen therapy for breast cancer

2006 ◽  
Vol 13 (3) ◽  
pp. 921-930 ◽  
Author(s):  
Daniele Generali ◽  
Stephen B Fox ◽  
Alfredo Berruti ◽  
Maria P Brizzi ◽  
Leticia Campo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multivariate Analysis ◽  
Carbonic Anhydrase ◽  
Cancer Patients ◽  
Tamoxifen Therapy ◽  
Carbonic Anhydrase Ix ◽  
Breast Cancer Patients ◽  
Caix Expression ◽  
Er Positive

The purpose of this study is to investigate the role of carbonic anhydrase IX (CAIX) expression in predicting the response to epirubicin and disease-free survival (DFS) in breast cancer patients enrolled in a single institution trial of primary anthracycline and tamoxifen therapy. CAIX expression was assessed in 183 patients with T2–4 N0–1 breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin + tamoxifen as primary systemic treatment. All patients received postoperatively four cycles of the four weekly i.v. cyclophosphamide, methotrexate, 5-fluorouracil regimen. Patients with estrogen receptor (ER)-positive primary tumors received 5 years of adjuvant tamoxifen. Pretreatment, p53 (P = 0.007), c-erbB2 (P < 0.01), and Ki67 (P = 0.02) were directly associated with CAIX expression, while bcl2 (P < 0.000) and ER (P = 0.000) and progesterone receptor (PgR; P < 0.01) were inversely correlated. In multivariate analysis, only high p53 and low bcl2 were independently associated with CAIX positivity. CAIX immunostaining was significantly associated with poor outcome for DFS (P < 0.002) and overall survival (P = 0.001). In multivariate analysis, a significant interaction was found between CAIX and markers of hormone sensitivity, bcl2 (P = 0.01), ER (P = 0.02), PgR (P = 0.02), and lymph node involvement (P = 0.04), in predicting DFS. Presently, there are few clinical markers of resistance to tamoxifen treatment in ER-positive tumors. CAIX expression in breast cancer patients shows a negative predictive role of treatment efficacy in ER-positive patients on the adjuvant tamoxifen after primary chemo-endocrine therapy. Studies investigating the effects of pH on tamoxifen uptake and the effects of therapy with CA inhibitors are planned.

Influence of IP-10/CXCL10 induction in human pancreatic cancer stroma on lymphocytes recruitment and correlation with survival.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 290-290 ◽  
Author(s):  
Thomas B Brunner ◽  
Serena Lunardi ◽  
Nigel B Jamieson ◽  
Su Yin Lim ◽  
Kristin L Griffiths ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Patients ◽  
Mononuclear Cells ◽  
Pancreatic Stellate Cells ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells

290 Background: Pancreatic ductal adenocarcinoma is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Methods: Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines, chemokines and growth factors. Gene expression analysis of human pancreatic ductal adenocarcinoma samples was used to verify expression of cytokines and their correlation with markers of immunoresponse and with clinical outcome. Finally, we tested chemotaxis of leukocytes isolated from peripheral blood mononuclear cells of pancreatic cancer patients. Results: IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 expression was consistently upregulated in human pancreatic cancer specimens, and positively correlated with high stroma content. Furthermore, expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, the survival of patients with high IP-10 levels was 18.1 months less than those with low IP-10 levels (HR=2.14, 95% CI 1.05 -4.42). Importantly, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with pancreatic cancer. Conclusions: Our findings suggest that, in pancreatic cancer patients, CXCR3+ Tregs are recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.

780: Carbonic Anhydrase IX (CAIX) Expression and VHL Gene Alteration as Predictors of Survival in Renal Cell Carcinoma

2004 ◽  
Vol 171 (4S) ◽  
pp. 206-207 ◽  
Author(s):  
Hideki Mukouyama ◽  
Masahiro Yao ◽  
David B. Seligson ◽  
John S. Lam ◽  
Yoji Nagashima ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Carbonic Anhydrase ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Carbonic Anhydrase Ix ◽  
Vhl Gene ◽  
Gene Alteration ◽  
Caix Expression

41 Cathepsin D Expression in Pancreatic Ductal Adenocarcinoma (PDAC) Cells Increases Proliferation and Reduces Survival of Pancreatic Cancer Patients

2015 ◽  
Vol 148 (4) ◽  
pp. S-13
Author(s):  
Ujjwal M. Mahajan ◽  
Enno Langhoff ◽  
Eithne Costello ◽  
William Greenhalf ◽  
Christopher Halloran ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Patients ◽  
Cathepsin D ◽  
Ductal Adenocarcinoma

scholarly journals Omics Approaches in Pancreatic Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1052
Author(s):  
Iranzu González-Boja ◽  
Antonio Viúdez ◽  
Saioa Goñi ◽  
Enrique Santamaria ◽  
Estefania Carrasco-García ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Survival Rate ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Curative Intent ◽  
Pancreatic Cancers ◽  
Wide Range ◽  
Prevention And Treatment ◽  
Shed Light

Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal—around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients.

Roles of Carbonic Anhydrase IX in Development of Pancreatic Cancer

2015 ◽  
Vol 22 (2) ◽  
pp. 277-286 ◽  
Author(s):  
Yuji Li ◽  
Ming Dong ◽  
Weiwei Sheng ◽  
Longping Huang
Keyword(s):  
Pancreatic Cancer ◽  
Carbonic Anhydrase ◽  
Carbonic Anhydrase Ix

scholarly journals Hypoxia-driven oncometabolite L-2HG maintains “stemness”-differentiation balance and facilitates immune suppression in pancreatic cancer

2020 ◽  
Author(s):  
Vineet K Gupta ◽  
Nikita S Sharma ◽  
Brittany Durden ◽  
Vanessa T Garrido ◽  
Kousik Kesh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell Activation ◽  
Immune Suppression ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Isomeric Form ◽  
Spectrometric Analysis ◽  
Self Renewal ◽  
Pancreatic Cancer Cells ◽  
First Time

Abstract2-hydroxyglutarate (2-HG) has gained considerable importance in glioma and blood cancers that have mutations in the IDH1/2 gene. In the current study we show for the first time that pancreatic tumors produce 2HG in the absence of IDH1/2 mutation. Our study shows that hypoxic pancreatic tumors that have activated lactate dehydrogenase (LDH) activity, produce the L-isoform of 2HG.Metabolic mass spectrometric analysis along with chiral derivatization showed that pancreatic cancer cells as well as stromal cells secrete the L-isomeric form of 2-hydroxyglutarate (L-2HG) when exposed to hypoxic environment. Serum analysis of human pancreatic cancer patients also showed similar accumulation of L-2HG. Our results showed that this abnormally accumulated L-2HG regulates self-renewal by increasing expression of genes associated with stemness (Sox-2, CD133) and by decreasing expression of differentiation genes (Pdx-1, HB9, NKX6.1). Further analysis showed that secreted L-2HG mediates cross talk with immune T-cells and hampers their proliferation and migration thereby suppressing the anti-tumor immunity. In vivo targeting of LDH enzyme with inhibitor (GSK2837808A) showed decrease in L-2HG as well as subsequent tumor regression and sensitization to immune-checkpoint therapy.Present study shows for the first time that hypoxia mediated accumulation of L-2HG drives self-renewal in pancreatic cancer by shifting critical balance of gene expression towards stemness and promotes immune suppression by impairing T cell activation in this disease. Additionally, it indicates that targeting LDH can sensitize pancreatic tumors to anti-PD1 therapy by decreasing L-2HG and reverting their immune evasive function.

scholarly journals Extracellular vesicles in pancreatic cancer progression and therapies

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Chao-Hui Chang ◽  
Siim Pauklin
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Delayed Diagnosis ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Ductal Adenocarcinoma ◽  
Cancer Hallmarks ◽  
Pancreatic Cancers

AbstractPancreatic cancer (PC) is one of the leading causes of cancer-related death worldwide due to delayed diagnosis and limited treatments. More than 90% of all pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC). Extensive communication between tumour cells and other cell types in the tumour microenvironment have been identified which regulate cancer hallmarks during pancreatic tumorigenesis via secretory factors and extracellular vesicles (EVs). The EV-capsuled factors not only facilitate tumour growth locally, but also enter circulation and reach distant organs to construct a pre-metastatic niche. In this review, we delineate the key factors in pancreatic ductal adenocarcinoma derived EVs that mediate different tumour processes. Also, we highlight the factors that are related to the crosstalk with cancer stem cells/cancer-initiating cells (CSC/CIC), the subpopulation of cancer cells that can efficiently metastasize and resist currently used chemotherapies. Lastly, we discuss the potential of EV-capsuled factors in early diagnosis and antitumour therapeutic strategies.

scholarly journals Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA

2018 ◽  
Author(s):  
Francois Collin ◽  
Yuhong Ning ◽  
Tierney Phillips ◽  
Erin McCarthy ◽  
Aaron Scott ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Early Stage ◽  
Training Data ◽  
Ductal Adenocarcinoma ◽  
Data Sets ◽  
Cell Free Dna ◽  
Non Invasive ◽  
Pancreatic Cancers ◽  
Free Dna ◽  
Circulating Cell Free Dna

AbstractPancreatic cancers are typically diagnosed at late stage where disease prognosis is poor as exemplified by a 5-year survival rate of 8.2%. Earlier diagnosis would be beneficial by enabling surgical resection or earlier application of therapeutic regimens. We investigated the detection of pancreatic ductal adenocarcinoma (PDAC) in a non-invasive manner by interrogating changes in 5-hydroxymethylation cytosine status (5hmC) of circulating cell free DNA in the plasma of a PDAC cohort (n=51) in comparison with a non-cancer cohort (n=41). We found that 5hmC sites are enriched in a disease and stage specific manner in exons, 3’UTRs and transcription termination sites. Our data show that 5hmC density is reduced in promoters and histone H3K4me3-associated sites with progressive disease suggesting increased transcriptional activity. 5hmC density is differentially represented in thousands of genes, and a stringently filtered set of the most significant genes points to biology related to pancreas (GATA4, GATA6, PROX1, ONECUT1) and/or cancer development (YAP1, TEAD1, PROX1, ONECUT1, ONECUT2, IGF1 and IGF2). Regularized regression models were built using 5hmC densities in statistically filtered genes or a comprehensive set of highly variable 5hmC counts in genes and performed with an AUC = 0.94-0.96 on training data. We were able to test the ability to classify PDAC and non-cancer samples with the Elastic net and Lasso models on two external pancreatic cancer 5hmC data sets and found validation performance to be AUC = 0.74-0.97. The findings suggest that 5hmC changes enable classification of PDAC patients with high fidelity and are worthy of further investigation on larger cohorts of patient samples.

scholarly journals Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma

2020 ◽  
Author(s):  
Allison N. Lau ◽  
Zhaoqi Li ◽  
Laura V. Danai ◽  
Anna M. Westermark ◽  
Alicia M. Darnell ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Heterogeneous Systems ◽  
Cell Types ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Specific Cell ◽  
Isolated Cells ◽  
Pancreatic Cancer Cells ◽  
Turn Over

AbstractTumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between various cell types within a mixed population can be limited by the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in pancreatic cancer organoid-fibroblast co-cultures and in pancreatic tumors. In these contexts, we find pancreatic cancer cells exhibit increased pyruvate carboxylation relative to fibroblasts, and that this flux depends on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells is necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tumor tissue.

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