Pancreatic Ductal Adenocarcinoma: Tumor Microenvironment and Problems in the Development of Novel Therapeutic Strategies

Overview

Journal Clin Exp Med

Specialty General Medicine

Date 2022 Sep 10

PMID 36085429

Authors

Alla Kuznetsova

Olga Popova

Dmitry Panchenkov

Tatyana Dyuzheva

Alexey Ivanov

Affiliations

Soon will be listed here.

Abstract

Diagnosis and treatment of carcinoma of the exocrine part of the pancreas is a serious problem for modern medicine. Despite the identification of a large number of aberrant mutations in pancreatic ductal adenocarcinoma (PDAC), attempts to create effective therapeutic agents based on identified genetic or epigenetic variations have not been succesful. The role of the tumor microenvironment (TME) in tumor progression is currently a popular topic. Cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) are the main components of the tumor stroma and play an important role in the proliferation, invasiveness and metastasis of cancer. However, the mechanisms underlying the effect of CAFs and ECM on cancer progression are still unclear. Recent studies on stromal components and blockage of signaling pathways have brought some optimism to this area. New information on the role of TME will lead to the development of targeted therapies or combinations with modern chemotherapy for PDAC.

Citing Articles

Multibiomarker panels in liquid biopsy for early detection of pancreatic cancer - a comprehensive review.

Reese K, Pantel K, Smit D J Exp Clin Cancer Res. 2024; 43(1):250.

PMID: 39218911 PMC: 11367781. DOI: 10.1186/s13046-024-03166-w.

Contemporary Approaches to Immunotherapy of Solid Tumors.

Kuznetsova A, Glukhova X, Popova O, Beletsky I, Ivanov A Cancers (Basel). 2024; 16(12).

PMID: 38927974 PMC: 11201544. DOI: 10.3390/cancers16122270.

Editorial: Organoids, organs-on-chip, nanoparticles and approaches to dissect the tumor-immune dynamics and to unveil the drug resistance mechanisms to therapy in the tumor microenvironment.

Mattei F, George J, Jolly M Front Immunol. 2023; 14:1253551.

PMID: 37533861 PMC: 10392942. DOI: 10.3389/fimmu.2023.1253551.

Leveraging Tumor Microenvironment Infiltration in Pancreatic Cancer to Identify Gene Signatures Related to Prognosis and Immunotherapy Response.

Yang J, Zeng L, Chen R, Huang L, Wu Z, Yu M Cancers (Basel). 2023; 15(5).

PMID: 36900234 PMC: 10000708. DOI: 10.3390/cancers15051442.

Pancreatic Organoids: A Frontier Method for Investigating Pancreatic-Related Diseases.

Liu Y, Li N, Zhu Y Int J Mol Sci. 2023; 24(4).

PMID: 36835437 PMC: 9959977. DOI: 10.3390/ijms24044027.

References

Siegel R, Miller K, Fuchs H, Jemal A . Cancer statistics, 2022. CA Cancer J Clin. 2022; 72(1):7-33. DOI: 10.3322/caac.21708. View

Biankin A, Waddell N, Kassahn K, Gingras M, Muthuswamy L, Johns A . Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012; 491(7424):399-405. PMC: 3530898. DOI: 10.1038/nature11547. View

Harris N, Vennin C, Conway J, Vine K, Pinese M, Cowley M . SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer. Oncogene. 2017; 36(30):4288-4298. PMC: 5537606. DOI: 10.1038/onc.2017.63. View

Haeberle L, Esposito I . Pathology of pancreatic cancer. Transl Gastroenterol Hepatol. 2019; 4:50. PMC: 6624347. DOI: 10.21037/tgh.2019.06.02. View

Ozdemir B, Pentcheva-Hoang T, Carstens J, Zheng X, Wu C, Simpson T . Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014; 25(6):719-34. PMC: 4180632. DOI: 10.1016/j.ccr.2014.04.005. View

Jacobetz M, Chan D, Neesse A, Bapiro T, Cook N, Frese K . Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2012; 62(1):112-20. PMC: 3551211. DOI: 10.1136/gutjnl-2012-302529. View

Ding C, Li Y, Xing C, Zhang H, Wang S, Dai M . Research Progress on Slit/Robo Pathway in Pancreatic Cancer: Emerging and Promising. J Oncol. 2020; 2020:2845906. PMC: 7341381. DOI: 10.1155/2020/2845906. View

Thomas D, Radhakrishnan P . Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis. Mol Cancer. 2019; 18(1):14. PMC: 6341551. DOI: 10.1186/s12943-018-0927-5. View

Basturk O, Hong S, Wood L, Adsay N, Albores-Saavedra J, Biankin A . A Revised Classification System and Recommendations From the Baltimore Consensus Meeting for Neoplastic Precursor Lesions in the Pancreas. Am J Surg Pathol. 2015; 39(12):1730-41. PMC: 4646710. DOI: 10.1097/PAS.0000000000000533. View

10.

Zhou D, Jayasinghe R, Chen S, Herndon J, Iglesia M, Navale P . Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer. Nat Genet. 2022; 54(9):1390-1405. PMC: 9470535. DOI: 10.1038/s41588-022-01157-1. View

11.

Abe K, Suda K, Arakawa A, Yamasaki S, Sonoue H, Mitani K . Different patterns of p16INK4A and p53 protein expressions in intraductal papillary-mucinous neoplasms and pancreatic intraepithelial neoplasia. Pancreas. 2007; 34(1):85-91. DOI: 10.1097/01.mpa.0000240608.56806.0a. View

12.

Nones K, Waddell N, Song S, Patch A, Miller D, Johns A . Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling. Int J Cancer. 2014; 135(5):1110-8. DOI: 10.1002/ijc.28765. View

13.

Bailey P, Chang D, Nones K, Johns A, Patch A, Gingras M . Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016; 531(7592):47-52. DOI: 10.1038/nature16965. View

14.

Buscail L, Bournet B, Cordelier P . Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2020; 17(3):153-168. DOI: 10.1038/s41575-019-0245-4. View

15.

Kotoula V, Charalambous E, Biesmans B, Malousi A, Vrettou E, Fountzilas G . Targeted KRAS mutation assessment on patient tumor histologic material in real time diagnostics. PLoS One. 2009; 4(11):e7746. PMC: 2768905. DOI: 10.1371/journal.pone.0007746. View

16.

Pietrobono S, Gagliardi S, Stecca B . Non-canonical Hedgehog Signaling Pathway in Cancer: Activation of GLI Transcription Factors Beyond Smoothened. Front Genet. 2019; 10:556. PMC: 6581679. DOI: 10.3389/fgene.2019.00556. View

17.

Mills L, Zhang Y, Marler R, Herreros-Villanueva M, Zhang L, Almada L . Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation. J Biol Chem. 2013; 288(17):11786-94. PMC: 3636867. DOI: 10.1074/jbc.M112.438846. View

18.

Kamerkar S, LeBleu V, Sugimoto H, Yang S, Ruivo C, Melo S . Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature. 2017; 546(7659):498-503. PMC: 5538883. DOI: 10.1038/nature22341. View

19.

Golan T, Zorde Khvalevsky E, Hubert A, Gabai R, Hen N, Segal A . RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients. Oncotarget. 2015; 6(27):24560-70. PMC: 4695206. DOI: 10.18632/oncotarget.4183. View

20.

Asati V, Mahapatra D, Bharti S . K-Ras and its inhibitors towards personalized cancer treatment: Pharmacological and structural perspectives. Eur J Med Chem. 2016; 125:299-314. DOI: 10.1016/j.ejmech.2016.09.049. View