Sammanfattning Inledning: Den årliga incidensen för pankreascancer är 9 per 100 000 invånare. En tidig diagnos ger förbättrad 5-årsöverlevnad men botar fortfarande få patienter. De senaste åren har den dåliga prognosen förbättras tack vare utvecklingen inom bilddiagnostiken. Författaren i denna litteraturstudie har valt att jämföra multidetektor datortomografi (MDCT) och magnetisk resonans (MR) med kontrastmedel för diagnostik av pankreastumör vid misstänkt pankreascancer. Syfte: Syftet med denna litteraturstudie är att undersöka vilken radiologisk undersökningsmetod som är att föredra vid diagnostisering av pankreascancer, MDCT eller MR. Frågeställning: Är det MDCT eller MR som är bäst vid diagnostisering av pankreascancer? Metod: En litteraturstudie baserad på 12 antal artiklar som är funna i databasen PubMed. Resultat: MDCT och MR har likvärdig diagnostisk säkerhet att upptäcka pankreastumör samt påvisa kärlinväxt och förutse operabilitet. Båda metoderna har en jämförbar hög noggrannhet för karakterisering av förändringens aggressivitet. Slutsats: Såväl MDCT och MR är likvärdiga två mycket bra radiologiska metoder för att diagnostisera pankreascancer. MDCT har fortfarande en större tillgänglighet är MR men dess nackdel är man utsätter patienterna för joniserande strålning. MR är därför en metod att föredra och med stor sannolikhet kommer dess tillgänglighet att öka kraftigt i framtiden.

Indiana University-Purdue University Indianapolis (IUPUI) / Pancreatic ductal adenocarcinoma (PDA) is a deadly disease due to early metastasis and resistance to chemotherapy. PDA is commonly associated with a dense desmoplastic stroma, which forms a protective niche for cancer cells. Tissue transglutaminase (TG2), a Ca2+-dependent enzyme, is abundantly expressed in pancreatic cancer cells and crosslinks proteins through acyl-transfer transamidation between glutamine and lysine residues. The objective of the study was to determine the functions of TG2 in the pancreatic stroma. Orthotopic pancreatic xenografts and co-culture systems tested the mechanisms by which the enzyme modulates tumor-stroma interactions. We showed that TG2 secreted by cancer cells is enzymatically active and renders the stroma denser by crosslinking collagen, which in turn activates fibroblasts and stimulates their proliferation. Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are transcription factors involved in mechanotransduction. The TG2-mediated fibrosis-rich, stiff microenvironment conveys mechanical cues to cancer cells leading to activation of YAP and TAZ, promoting cell proliferation and tumor growth. Stable knockdown of TG2 in pancreatic cancer cells led to decreased size of pancreatic xenografts and increased sensitivity of xenografts to gemcitabine. Taken together, our results demonstrate that TG2 secreted in the tumor microenvironment orchestrates the crosstalk between cancer cells and the stroma, fundamentally impacting tumor growth and response to chemotherapy. Our study supports TG2 inhibition in the pancreatic stroma as a novel strategy to block pancreatic cancer progression.

Indiana University-Purdue University Indianapolis (IUPUI) / Pancreatic ductal adenocarcinoma (PDAC), which comprises 85% of pancreatic cancers, is the 4th leading cause of cancer death in the United States with a 5-year survival rate of 8%. While human PDACs (hPDACs) are hypovascular, they also overexpress a number of angiogenic growth factors and receptors. Additionally, the use of anti-angiogenic agents in murine models of PDAC leads to reduced tumor volume, tumor spread, and microvessel density (MVD), and improved survival. Nonetheless, clinical trials using anti-angiogenic therapy have been overwhelmingly unsuccessful in hPDAC. On the other hand, pancreatic neuroendocrine tumors (PNETs) account for only 2% of pancreatic tumors, yet they are very vascular and classically angiogenic, respond to anti-angiogenic therapy, and confer a better prognosis than PDAC even in the metastatic setting. In an effort to compare and contrast the angiogenic transcriptomes of these two tumor types, we analyzed RNA-Sequencing (RNA-Seq) data from The Cancer Genome Atlas (TCGA) and found that a pro-angiogenic gene signature is present in 35% of PDACs and that it is mostly distinct from the angiogenic signature present in PNETs. The pro-angiogenic PDAC subgroup also exhibits a transcriptome that reflects active TGF-β signaling, less frequent SMAD4 inactivation than PDACs without the signature, and up-regulation of several pro-inflammatory genes, including members of JAK signaling pathways. Consequently, targeting the TGF-β receptor type-1 kinase with SB505124 and JAK1/2 with ruxolitinib blocks proliferative crosstalk between human pancreatic cancer cells (PCCs) and human endothelial cells (ECs). Additionally, treatment of the KRC (oncogenic Kras, homozygous deletion of Rb1) and KPC (oncogenic Kras, mutated Trp53) genetically engineered PDAC mouse models with ruxolitinib suppresses murine PDAC (mPDAC) progression only in the KRC model, which shows superior enrichment and differential expression of the human pro-angiogenic gene signature as compared to KPC tumors. These findings suggest that targeting both TGF-β and JAK signaling in the 35% of PDAC patients whose cancers exhibit an pro-angiogenic gene signature should be explored in a clinical trial.