The stellate cancer-associated fibroblast in pancreatic ductal adenocarcinoma; its role in chemoresistance

摘要

Introduction: The tumour microenvironment has been found to contribute to cancerudsurvival and progression, and more specifically, the stromal microenvironment hasudbeen implicated in the drug resistant nature of cancers such as pancreatic cancer.udThis microenvironment consists of fibroblasts, pericytes, endothelial cells and theudextracellular matrix, with the stellate cancer-associated fibroblast (CAF) being theudmost predominant cell type present. The aim of this study was to investigate the roleudof the cancer associated fibroblast in tumourigenesis in Pancreatic DuctaludAdenocarcinoma (PDA) with specific reference to the mechanisms involved inudchemoresistance via the stellate cancer associated fibroblast.udMethods: I investigated the molecular pathogenesis of PDA assessing DNA copyudnumber alterations (CNA) in selection of clinically relevant PDA cell lines (PANC-1,udMiaPaCa-2, ASPC-1, SU86.86, HPAC, HS776T, PL5 and PL45), seven primaryudresected, non immortalised samples (PF3, PF7, PF8, PF9, PF16, PF18 and PF20)udand an immortalised stellate cell line using array comparative genomic hybridizationud(aCGH). All cultures and cell lines were then screened in order to determine theirudsensitivity to currently used therapeutic compounds. Analysis was done using Rudsoftware and Graph Pad Prism 5.udResults: The non-immortalised stellate CAFs and formalin fixed paraffin embeddedudstromal fibroblast samples showed no homozygous genomic CNAs. The stellateudcancer associated fibroblasts both primary and immortalised appear moreudresponsive to the chemotherapeutic drugs in the compound library compared to theudPDA cell lines.udConclusions: This study suggests the absence of homozygous deletions that mayudlead to a change in phenotype in the stellate CAF. However, the presence ofudheterozygous deletions and epigenetic changes has not yet been excluded. Furtherudexperiments such as micro RNA and epigenetic studies, such as SNP arrays, mayudidentify the presence of aberrations that have aetiological significance inudcarcinogenesis even if they do not result in CNVs. This higher sensitivity of theudstellate CAF to the drugs in the chemotherapy library may favour them as potentialudtargets for management of this hard to street subtype of disease.