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pancreatic cancer microenvironment

Constantinos Roufas, Dimitrios Chasiotis, Anestis Makris, Christodoulos Efstathiades, Christos Dimopoulos, Apostolos Zaravinos
Background: Recently, immune-checkpoint blockade has shown striking clinical results in different cancer patients. However, a significant inter-individual and inter-tumor variability exists among different cancers. The expression of the toxins granzyme A (GZMA) and perforin 1 (PRF1), secreted by effector cytotoxic T cells and natural killer (NK) cells, were recently used as a denominator of the intratumoral immune cytolytic activity (CYT). These levels are significantly elevated upon CD8+ T-cell activation as well as during a productive clinical response against immune-checkpoint blockade therapies...
2018: Frontiers in Oncology
Kei Takahashi, Shogo Ehata, Daizo Koinuma, Yasuyuki Morishita, Manabu Soda, Hiroyuki Mano, Kohei Miyazono
Tumor microenvironment plays a pivotal role in cancer progression; however, little is known regarding how differences in the microenvironment affect characteristics of cancer cells. Here, we investigated the effects of tumor microenvironment on cancer cells by using mouse tumor models. After three cycles of inoculation and extraction of human pancreatic cancer cells, including SUIT-2 and Panc-1 cells, from tumors, distinct cancer cell lines were established: 3P cells from the pancreas obtained using the orthotopic tumor model and 3sc cells from subcutaneous tissue obtained using the subcutaneous tumor model...
March 7, 2018: Oncogene
Vito Longo, Roberto Tamma, Oronzo Brunetti, Salvatore Pisconti, Antonella Argentiero, Nicola Silvestris, Domenico Ribatti
Mast cells are recognized as critical components of the tumor stromal microenvironment in several solid and hematological malignancies, promoting angiogenesis and tumor growth. A correlation between mast cells infiltration, angiogenesis and tumor progression has been reported for pancreatic ductal adenocarcinoma as well. Mast cells contribute to the aggressiveness of the pancreatic ductal carcinoma enhancing the expression of several pro-angiogenic factors such as vascular endothelial growth factor, fibroblast growth factor-2, platelet-derived growth factor and angiopoietin-1 as well as stimulating the pancreatic cancer cells proliferation by IL-13 and tryptase...
February 28, 2018: Clinical and Experimental Medicine
Shuo Chen, Xi Chen, Tao Shan, Jiancang Ma, Wanrun Lin, Wei Li, Ya'an Kang
In this study, we investigated whether the metabolic alteration of cancer-associated fibroblasts (CAFs) occurs via miR-21 remodeling and the effect of this alteration on pancreatic cancer cells. CAFs and normal fibroblasts (NFs) were isolated and cultured. Glucose consumption and lactic acid production were tested, and lactate dehydrogenase (LDHA), pyruvate kinase m2 (PKM2), and miR-21 expression were examined. The level of glycolysis in CAFs was determined after treatment with a miR-21 inhibitor. Primary miR-21-NC CAFs and miR-21-inhibitor CAFs were indirectly co-cultured with BxPc-3 in vitro , and the invasion capacity of these cells was determined...
2018: International Journal of Biological Sciences
Digdem Yoyen-Ermis, Kivilcim Ozturk-Atar, Muammer Alper Kursunel, Cisel Aydin, Didem Ozkazanc, Mustafa G Uuml Rb Uuml Z, Aysegul Uner, Metin Tulu, Sema Calis, Gunes Esendagli
While reshaping its microenvironment, tumors are also capable of influencing systemic processes such as myeloid cell production. Therefore, the tumor-induced myeloid cells, such as myeloid-derived suppressor cells (MDSCs) which are characterized with pro-cancer properties, became another target in order to increase success of the therapy. This study evaluated the capacity of a novel dendrimeric drug delivery platform to eliminate tumor-induced myeloid cells. As described in a previous study by our research group, the anti-Flt1 antibody-conjugated polyethylene glycol (PEG)-cored poly(amidoamine) (PAMAM) dendrimers improved the efficacy of gemcitabine against pancreatic cancer...
February 26, 2018: Molecular Pharmaceutics
Andreas Stylianou, Vasiliki Gkretsi, Triantafyllos Stylianopoulos
BACKGROUND: Tumor microenvironment consists of the extracellular matrix (ECM), stromal cells, such as fibroblasts-FBs and cancer associated fibroblasts-CAFs, and a myriad of soluble factors. In many tumor types, including pancreatic tumors, the interplay between stromal cells and the other tumor microenvironment components leads to desmoplasia, a cancer-specific type of fibrosis that hinders treatment. Transforming growth factor beta (TGF-β) and CAFs are thought to play a crucial role in this tumor desmoplastic reaction, although the involved mechanisms are unknown...
February 22, 2018: Biochimica et Biophysica Acta
Maria Kalli, Panagiotis Papageorgis, Vasiliki Gkretsi, Triantafyllos Stylianopoulos
Pancreatic fibroblasts are continuously gaining ground as an important component of tumor microenvironment that dynamically interact with cancer cells to promote tumor progression. In addition, these tumor-infiltrated fibroblasts can acquire an activated phenotype and produce excessive amounts of extracellular matrix creating a highly dense stroma, a situation known as desmoplasia. Desmoplasia, along with the uncontrolled proliferation of cancer cells, leads to the development of compressive forces within the tumor, generating the so-called solid stress...
February 22, 2018: Annals of Biomedical Engineering
Daniel Ansari, Helmut Friess, Monika Bauden, Johan Samnegård, Roland Andersson
Pancreatic cancer is known for its propensity to metastasize. Recent studies have challenged the commonly held belief that pancreatic cancer is a stepwise process, where tumor cells disseminate late in primary tumor development. Instead it has been suggested that pancreatic tumor cells may disseminate early and develop independently and in parallel to the primary tumor. Circulating tumor cells can be found in most patients with pancreatic cancer, even in those with localized stage. Also, recent phylogenetic analyses have revealed evidence for a branched evolution where metastatic lineages can develop early in tumor development...
January 19, 2018: Oncotarget
Song Han, David H Gonzalo, Michael Feely, Carlos Rinaldi, Sayali Belsare, Haiyan Zhai, Krishan Kalra, Michael H Gerber, Christopher E Forsmark, Steven J Hughes
The biology of tumor-associated stroma (TAS) in pancreatic ductal adenocarcinoma (PDAC) is not well understood. The paradoxical observation that stroma-depletion strategies lead to progression of PDAC reinforced the need to critically evaluate the functional contribution of TAS in the initiation and progression of PDAC. PDAC and TAS cells are unique in their expression of specific miRNAs, and this specific miRNA expression pattern alters host to tumor microenvironment interactions. Using primary human pancreatic TAS cells and primary xenograft PDAC cells co-culture, we provide evidence of miRNA trafficking and exchanging between TAS and PDAC cells, in a two-way, cell-contact independent fashion, via extracellular vesicles (EVs) transportation...
January 19, 2018: Oncotarget
Paola Cappello, Claudia Curcio, Giorgia Mandili, Cecilia Roux, Sara Bulfamante, Francesco Novelli
Pancreatic Ductal Adenocarcinoma (PDA) is an almost incurable radio- and chemo-resistant tumor, and its microenvironment is characterized by a strong desmoplastic reaction associated with a significant infiltration of T regulatory lymphocytes and myeloid-derived suppressor cells (Tregs, MDSC). Investigating immunological targets has identified a number of metabolic and cytoskeletal related molecules, which are typically recognized by circulating antibodies. Among these molecules we have investigated alpha-enolase (ENO1), a glycolytic enzyme that also acts a plasminogen receptor...
February 16, 2018: Cancers
Shu-Ta Wu, Chandra D Williams, Priyanka A Grover, Laura J Moore, Pinku Mukherjee
Pancreatic ductal adenocarcinoma (PDA) is the fourth-leading cause of cancer death in the United States with a 5-year overall survival rate of 8% for all stages combined. But this decreases to 3% for the majority of patients that present with stage IV PDA at time of diagnosis. The lack of distinct early symptoms for PDA is one of the primary reasons for the late diagnosis. Common symptoms like weight loss, abdominal and back pains, and jaundice are often mistaken for symptoms of other issues and do not appear until the cancer has progressed to a late stage...
2018: PloS One
Michael Dougan, Jessica R Ingram, Hee-Jin Jeong, Munir M Mosaheb, Patrick T Bruck, Lestat Ali, Novalia Pishesha, Olga Blomberg, Paul M Tyler, Mariah M Servos, Mohammad Rashidian, Quang-De Nguyen, Ulrich H von Andrian, Hidde L Ploegh, Stephanie K Dougan
Cytokine-based therapies for cancer have not achieved widespread clinical success because of inherent toxicities. Treatment for pancreatic cancer is limited by the dense stroma that surrounds tumors and by an immunosuppressive tumor microenvironment. To overcome these barriers, we developed constructs of single-domain antibodies (VHHs) against PD-L1 fused with IL2 and IFNgamma. Targeting cytokine delivery in this manner reduced pancreatic tumor burden by 50%, whereas cytokines fused to an irrelevant VHH, or blockade of PD-L1 alone, showed little effect...
February 19, 2018: Cancer Immunology Research
Yaojie Fu, Shanshan Liu, Shan Zeng, Hong Shen
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases worldwide. It is refractory to conventional treatments, and consequently has a documented 5-year survival rate as low as 7%. Increasing evidence indicates that activated pancreatic stellate cells (PSCs), one of the stromal components in tumor microenvironment (TME), play a crucial part in the desmoplasia, carcinogenesis, aggressiveness, metastasis associated with PDAC. Despite the current understanding of PSCs as a "partner in crime" to PDAC, detailed regulatory roles of PSCs and related microenvironment remain obscure...
February 19, 2018: Molecular Cancer
Yoko Fujii-Nishimura, Ken Yamazaki, Yohei Masugi, Junya Douguchi, Yutaka Kurebayashi, Naoto Kubota, Hidenori Ojima, Minoru Kitago, Masahiro Shinoda, Akinori Hashiguchi, Michiie Sakamoto
Epithelial-mesenchymal transition (EMT) promotes invasion and metastasis of pancreatic ductal adenocarcinoma (PDAC). However, the importance of its reverse process, mesenchymal-epithelial transition (MET), for PDAC remains unclear. We aimed to characterize the histological finding "focal differentiation" in PDAC at perineural invasion sites in the context of MET and to investigate the role of Schwann cells in inducing tumor MET. Tumor differentiation and immunohistochemical expressions of E-cadherin, SMAD3, and vimentin at perineural invasion sites were examined in 168 PDAC tissues...
February 19, 2018: Pathology International
Jonathan R Brody, Dan A Dixon
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with dismal patient outcomes. The underlying core genetic drivers of disease have been identified in human tumor specimens and described in genetically engineered mouse models. These genetic drivers of PDAC include KRAS signaling, TP53 mutations, and genetic loss of the SMAD4 tumor suppressor protein. Beyond the known mutational landscape of PDAC genomes, alternative disrupted targets that extend beyond conventional genetic mutations have been elusive and understudied in the context of PDAC cell therapeutic resistance and survival...
February 16, 2018: Wiley Interdisciplinary Reviews. RNA
Divya Chakravarthy, Amanda R Muñoz, Angel Su, Rosa F Hwang, Brian R Keppler, Daniel E Chan, Glenn Halff, Rita Ghosh, Addanki P Kumar
Reciprocal interaction between pancreatic stellate cells (PSCs) and cancer cells (PCCs) in the tumor microenvironment (TME) promotes tumor cell survival and progression to lethal, therapeutically resistant pancreatic cancer. The goal of this study was to test the ability of Palmatine (PMT) to disrupt this reciprocal interaction in vitro and examine the underlying mechanism of interaction. We show that PSCs secrete glutamine into the extracellular environment under nutrient deprivation. PMT suppresses glutamine-mediated changes in GLI signaling in PCCs resulting in the inhibition of growth and migration while inducing apoptosis by inhibition of survivin...
January 31, 2018: Cancer Letters
Amanda R Muñoz, Divya Chakravarthy, Jingjing Gong, Glenn A Halff, Rita Ghosh, Addanki P Kumar
Purpose of the review: The 5-year survival rate of patients with pancreatic cancer (PanCA) has remained stagnant. Unfortunately, the incidence is almost equal to mortality rates. These facts underscore the importance of concerted efforts to understand the pathology of this disease. Deregulation of multiple signaling pathways involved in a wide variety of cellular processes including proliferation, apoptosis, invasion, and metastasis contribute not only to cancer development but also to therapeutic resistance...
December 2017: Current Pharmacology Reports
Evangelia Sereti, Theodosia Karagianellou, Ioanna Kotsoni, Dimitrios Magouliotis, Konstantinos Kamposioras, Engin Ulukaya, Nikos Sakellaridis, Dimitrios Zacharoulis, Konstantinos Dimas
The prognosis of pancreatic ductal adenocarcinoma (PDAC), the eighth most lethal cancer for men and ninth for women worldwide, remains dismal. The increasing rates of deaths by PDAC indicate that the overall management of the disease in 21st century is still insufficient. Thus it is obvious that there is an unmet need to improve management of PDAC by finding new biomarkers to screen high risk patients, confirm diagnosis, and predict response to treatment as well more efficacious and safer treatments. Patient Derived Xenografts (PDX) have been developed as a new promising tool in an effort to mirror genetics, tumor heterogeneity and cancer microenvironment of the primary tumor...
February 1, 2018: Journal of Proteomics
Yiyin Zhang, Chao Yang, He Cheng, Zhiyao Fan, Qiuyi Huang, Yu Lu, Kun Fan, Guopei Luo, Kaizhou Jin, Zhengshi Wang, Chen Liu, Xianjun Yu
A poor prognosis of pancreatic ductal adenocarcinoma (PDAC) associated with chemoresistance has not changed for the past three decades. A multidisciplinary diagnosis followed by surgery and chemo(radiation)therapy is the main treatment approach. However, gemcitabine- and 5-fluorouracil-based therapies did not present satisfying outcomes. Novel regimens targeting pancreatic cancer cells, the tumor microenvironment, and immunosuppression are emerging. Biomarkers concerning the treatment outcome and patient selection are being discovered in preclinical or clinical studies...
January 31, 2018: Journal of Hematology & Oncology
Jiajia Zhang, Christopher L Wolfgang, Lei Zheng
Pancreatic cancer, most commonly referring to pancreatic ductal adenocarcinoma (PDAC), remains one of the most deadly diseases, with very few effective therapies available. Emerging as a new modality of modern cancer treatments, immunotherapy has shown promises for various cancer types. Over the past decades, the potential of immunotherapy in eliciting clinical benefits in pancreatic cancer have also been extensively explored. It has been demonstrated in preclinical studies and early phase clinical trials that cancer vaccines were effective in eliciting anti-tumor immune response, but few have led to a significant improvement in survival...
January 30, 2018: Cancers
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