The Role of Microtubules in Pancreatic Cancer: Therapeutic Progress

Pancreatic cancer has an extremely low prognosis, which is attributable to its high aggressiveness, invasiveness, late diagnosis, and lack of effective therapies. Among all the drugs joining the fight against this type of cancer, microtubule-targeting agents are considered to be the most promising. They inhibit cancer cells although through different mechanisms such as blocking cell division, apoptosis induction, etc. Hereby, we review the functions of microtubule cytoskeletal proteins in tumor cells and comprehensively examine the effects of microtubule-targeting agents on pancreatic carcinoma.

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Growth Hormone Receptor Inhibition Sensitizes Human Pancreatic Cancer to Chemotherapy Treatments

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.2086 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A1019-A1020

Author(s):

Reetobrata Basu ◽

John Joseph Kopchick ◽

Silvana Duran Ortiz ◽

Yanrong Qian ◽

Prateek Kulkarni

Keyword(s):

Pancreatic Cancer ◽

Growth Hormone ◽

Cancer Cells ◽

Tumor Cells ◽

Hormone Receptor ◽

Growth Hormone Receptor ◽

Human Pancreatic Cancer ◽

Drug Efflux ◽

Pancreatic Cancer Cells

Abstract Human growth hormone (GH) and its cognate growth hormone receptor (GHR) have been established to have a distinct role in promoting the progression of several types of human cancers. We had earlier described a newfound role of the GH-GHR axis in driving chemoresistance in melanoma by upregulating drug efflux by ABC multidrug transporter expression and a phenotype switch by induction of epithelial-to-mesenchymal transition (EMT). Here we present an in-depth analysis of this role of GH-GHR in the highly therapy resistant human pancreatic cancer which has a 5-year survival rate of only 10% in 2020. Using human and mouse pancreatic cancer cells and RNA and protein expression analyses by RT-qPCR, ELISA, and western-blot, we identified that (i) GH upregulates specific ABC-transporter expressions in a drug-context specific manner, (ii) GH upregulates EMT transcription factors, (iii) GH activates specific oncogenic signaling pathways, and (iii) GH action increases cytochrome P450 members involved in hepatic drug metabolism. The GH antagonist, Pegvisomant, significantly inhibited these effects. Additionally, we confirmed the effects of these molecular changes by specific assays. For example, GH increases basement membrane invasion, viability of circulating tumor cells, and drug efflux; while inhibition of GHR by pegvisomant in pancreatic cancer cells reversed this aggressive tumor phenotype and sensitized the tumor cells to chemotherapy. Cell viability assays confirmed a decreased IC50 of gemcitabine, doxorubicin, and erlotinib in pancreatic cancer cells treated with pegvisomant and an increase in IC50 cells treated with GH. We further verified our results using in silico analyses of TCGA datasets for pancreatic cancer - which provided robust confirmation of our experimental findings. Presently we are validating our observation in nude mice with human pancreatic cancer cell xenografts. In conclusion, our in vitro results confirm that GHR antagonism can drastically sensitize human pancreatic cancer cells by blocking mechanisms of drug resistance, thus providing a valuable window for improved efficacy of available chemo- and targeted therapy.

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Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts

Oncogenesis ◽

10.1038/s41389-020-00285-9 ◽

2020 ◽

Vol 9 (11) ◽

Author(s):

Pawan Noel ◽

Shaimaa Hussein ◽

Serina Ng ◽

Corina E. Antal ◽

Wei Lin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Antitumor Activity ◽

Cancer Cells ◽

Tumor Cells ◽

Stromal Cells ◽

Cancer Associated Fibroblasts ◽

Cell Type ◽

Pancreatic Cancer Cells ◽

Cell Type Specific

Abstract The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is highly heterogeneous, fibrotic, and hypovascular, marked by extensive desmoplasia and maintained by the tumor cells, cancer-associated fibroblasts (CAFs) and other stromal cells. There is an urgent need to identify and develop treatment strategies that not only target the tumor cells but can also modulate the stromal cells. A growing number of studies implicate the role of regulatory DNA elements called super-enhancers (SE) in maintaining cell-type-specific gene expression networks in both normal and cancer cells. Using chromatin activation marks, we first mapped SE networks in pancreatic CAFs and epithelial tumor cells and found them to have distinct SE profiles. Next, we explored the role of triptolide (TPL), a natural compound with antitumor activity, in the context of modulating cell-type-specific SE signatures in PDAC. We found that TPL, cytotoxic to both pancreatic tumor cells and CAFs, disrupted SEs in a manner that resulted in the downregulation of SE-associated genes (e.g., BRD4, MYC, RNA Pol II, and Collagen 1) in both cell types at mRNA and protein levels. Our observations suggest that TPL acts as a SE interactive agent and may elicit its antitumor activity through SE disruption to re-program cellular cross talk and signaling in PDAC. Based on our findings, epigenetic reprogramming of transcriptional regulation using SE modulating compounds such as TPL may provide means for effective treatment options for pancreatic cancer patients.

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Role of exosomes in diagnosis and therapy of prostate cancer

I P Pavlov Russian Medical Biological Herald ◽

10.23888/pavlovj2020283399-405 ◽

2020 ◽

Vol 28 (3) ◽

pp. 399-405

Author(s):

Fabrizio Fontana ◽

Olga A. Babenko

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Biological Fluids ◽

Diagnosis And Treatment ◽

Diagnosis And Therapy ◽

The Future ◽

Important Direction ◽

Potential Biomarkers

Aim of this letter is to attract the attention of journal readers to the study of exosomes as an important direction in the development of Oncology, in particular, in the diagnosis and treatment of prostate cancer. Exosomes are produced by tumor cells and regulate proliferation, metastasis, and the development of chemoresistance. Their extraction from biological fluids allows further use of these vesicles as potential biomarkers of prostate cancer. In the future, exosomes can be successfully used in the delivery of drugs and other anti-tumor substances to cancer cells.

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Emerging roles of cancer-testis antigenes, semenogelin 1 and 2, in neoplastic cells

Cell Death Discovery ◽

10.1038/s41420-021-00482-4 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Oleg Shuvalov ◽

Alyona Kizenko ◽

Alexey Petukhov ◽

Olga Fedorova ◽

Alexandra Daks ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Reproductive System ◽

Seminal Fluid ◽

Cancer Development ◽

Migration And Invasion ◽

Malignant Cells ◽

Cancer Testis

AbstractCancer-testicular Antigens (CTAs) belong to a group of proteins that under normal conditions are strictly expressed in a male’s reproductive tissues. However, upon malignisation, they are frequently re-expressed in neoplastic tissues of various origin. A number of studies have shown that different CTAs affect growth, migration and invasion of tumor cells and favor cancer development and metastasis. Two members of the CTA group, Semenogelin 1 and 2 (SEMG1 and SEMG2, or SEMGs) represent the major component of human seminal fluid. They regulate the motility and capacitation of sperm. They are often re-expressed in different malignancies including breast cancer. However, there is almost no information about the functional properties of SEMGs in cancer cells. In this review, we highlight the role of SEMGs in the reproductive system and also summarize the data on their expression and functions in malignant cells of various origins.

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Contribution of the CK2 Catalytic Isoforms α and α’ to the Glycolytic Phenotype of Tumor Cells

Cells ◽

10.3390/cells10010181 ◽

2021 ◽

Vol 10 (1) ◽

pp. 181

Author(s):

Francesca Zonta ◽

Christian Borgo ◽

Camila Paz Quezada Meza ◽

Ionica Masgras ◽

Andrea Rasola ◽

...

Keyword(s):

Cell Proliferation ◽

Protein Kinase ◽

Cancer Cells ◽

Tumor Cells ◽

Therapeutic Strategies ◽

The Other ◽

Osteosarcoma Cell ◽

Monomeric Form ◽

New Information

CK2 is a Ser/Thr protein kinase overexpressed in many cancers. It is usually present in cells as a tetrameric enzyme, composed of two catalytic (α or α’) and two regulatory (β) subunits, but it is active also in its monomeric form, and the specific role of the different isoforms is largely unknown. CK2 phosphorylates several substrates related to the uncontrolled proliferation, motility, and survival of cancer cells. As a consequence, tumor cells are addicted to CK2, relying on its activity more than healthy cells for their life, and exploiting it for developing multiple oncological hallmarks. However, little is known about CK2 contribution to the metabolic rewiring of cancer cells. With this study we aimed at shedding some light on it, especially focusing on the CK2 role in the glycolytic onco-phenotype. By analyzing neuroblastoma and osteosarcoma cell lines depleted of either one (α) or the other (α’) CK2 catalytic subunit, we also aimed at disclosing possible pro-tumor functions which are specific of a CK2 isoform. Our results suggest that both CK2 α and α’ contribute to cell proliferation, survival and tumorigenicity. The analyzed metabolic features disclosed a role of CK2 in tumor metabolism, and suggest prominent functions for CK2 α isoform. Results were also confirmed by CK2 pharmacological inhibition. Overall, our study provides new information on the mechanism of cancer cells addiction to CK2 and on its isoform-specific functions, with fundamental implications for improving future therapeutic strategies based on CK2 targeting.

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Patterns and Relevance of Langerhans Islet Invasion in Pancreatic Cancer

Cancers ◽

10.3390/cancers13020249 ◽

2021 ◽

Vol 13 (2) ◽

pp. 249

Author(s):

Ruediger Goess ◽

Ayse Ceren Mutgan ◽

Umut Çalışan ◽

Yusuf Ceyhun Erdoğan ◽

Lei Ren ◽

...

Keyword(s):

Diabetes Mellitus ◽

Pancreatic Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Islet Cells ◽

Human Pancreatic Cancer ◽

Type I ◽

Type Iv ◽

Pancreatic Cancer Cells

Background: Pancreatic cancer‐associated diabetes mellitus (PC‐DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patientswith pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to isletcells. Results: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri‐insular invasion with tumor cells directly touching the boundary, but not penetrating the islet; (Type II) endo‐insular invasion with tumor cells inside the round islet; (Type III) distorted islet structure with complete loss of the round islet morphology; and (Type IV)adjacent cancer and islet cells with solitary islet cells encountered adjacent to cancer cells. Pancreatic cancer cells did not exhibit any chemoattraction to islet cells in 3D assays in vitro. Further, there was no clinical correlation of islet invasion using the novel Islet Invasion Severity Score (IISS), which includes all invasion patterns with the occurrence of diabetes mellitus. However, Type IV islet invasion was related to worsened overall survival in our cohort. Conclusions: We systematically analyzed, for the first time, islet invasion in human pancreatic cancer. Four different main patterns of islet invasion were identified. Diabetes mellitus was not related to islet invasion. However, moreresearch on this prevailing feature of pancreatic cancer is needed to better understand underlying principles.

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The Role of Radiotherapy for Pancreatic Malignancies- A Population-based Analysis of the SEER-Medicare Database.

10.21203/rs.3.rs-120622/v1 ◽

2020 ◽

Author(s):

yunxiu luo ◽

Shengjun Xiao

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Carcinoma ◽

Adjuvant Radiotherapy ◽

Adenosquamous Carcinoma ◽

Early Stage ◽

Pancreatic Head ◽

Population Based ◽

Anatomical Location ◽

Duct Carcinoma

Abstract Background and objective. To investigate the role of adjuvant radiotherapy in patients after surgical resection for pancreatic cancer. Methods and patients. The patients with pancreatic cancer from 18 registered institutions in the Surveillance Epidemiology and End Results (SEER) database were retrospectively analyzed. The characteristics of patients who would benefit from adjuvant radiotherapy were screened, as well as whether neoadjuvant or adjuvant radiotherapy conferred to a better clinical outcome. Results. 30249 patients included in this study (21295 vs 8954 in surgery and adjuvant radiotherapy group) .The median survivals in the surgery (S) group and adjuvant radiotherapy (S+R) group were 24 and 21 months respectively, The 1, 3, and 5-year overall survival (OS) rates in the S group and S+R group were 68%, 40%, 31% ,and 75%, 30%, 20%, respectively (p<0.001).Stratified analysis showed patients with histological classified as adenocarcinoma(15 VS 21, P<0.0001), infiltrating duct carcinoma (17 VS 21,P<0.0001), adenosquamous carcinoma(10 VS 18,P<0.0001) could be benefit from adjuvant radiotherapy. Adjuvant radiotherapy was helpful to improve the OS for patients with pancreatic head (19 VS 21, P=0.0003) and duct carcinoma (18VS 28, P=0.0121). Subgroup stratified assay indicated specific patients with early stage (AJCC 7th I, II, T2, N0) pancreatic carcinoma had better OS after additional radiotherapy than surgery alone. Conclusion. Additional radiotherapy may contribute to improved prognosis for patients with pancreatic carcinoma of specific histological types (adenocarcinoma/carcinoma, infiltrating duct carcinoma, adenosquamous carcinoma, and squamous), anatomical location, and advanced stage. A specific subgroup of patients with an early stage (I/II, T2) pancreatic cancer should be considered for additional radiotherapy.

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