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Pancreatic cancer – Influence of Tumour Microenvironment

Gundewar, Chinmay LU (2015) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:66.
Abstract (Swedish)
Popular Abstract in Swedish

Pankreascancer (cancer i bukspottkörteln) utgör fjärde orsak död i cancer. Det är den cancerform som har den dystraste prognosen av alla, med en 5-års överlevnad mindre än 6%. Sjukdomsrelaterade symptom uppträder ofta sent i förloppet och det saknas metoder för tidig diagnos varför de flesta av patienterna upptäckts i sent skede. Endast cirka 20 procent av patienterna kan bli föremål för kurativt syftande kirurgi men av dessa kommer flertalet få återfall i sin sjukdom. För de allra flesta patienterna är onkologisk behandling aktuell, antingen som tilläggsbehandling efter kirurgi eller i palliativt syfte. Cellgiftsbehandling har visats ge överlevnadsvinster

men nyttan är endast marginell... (More)
Popular Abstract in Swedish

Pankreascancer (cancer i bukspottkörteln) utgör fjärde orsak död i cancer. Det är den cancerform som har den dystraste prognosen av alla, med en 5-års överlevnad mindre än 6%. Sjukdomsrelaterade symptom uppträder ofta sent i förloppet och det saknas metoder för tidig diagnos varför de flesta av patienterna upptäckts i sent skede. Endast cirka 20 procent av patienterna kan bli föremål för kurativt syftande kirurgi men av dessa kommer flertalet få återfall i sin sjukdom. För de allra flesta patienterna är onkologisk behandling aktuell, antingen som tilläggsbehandling efter kirurgi eller i palliativt syfte. Cellgiftsbehandling har visats ge överlevnadsvinster

men nyttan är endast marginell och endast en liten andel av patienterna svarar på given cellgiftsbehandling.



Pankreascancer kännetecknas av en uttalad bindvävsreaktion (stroma) som omger och infiltrerar tumörcellerna. Stromat bidrar till att skapa en tumörmikromiljö som är gynnsam för tumören genom att bidra till tumörtillväxt och cellgiftsresistens. Trots att stromat har en central betydelse vid pankreascancer, är de cellulära och molekylära faktorerna som bidrar till stromareaktionen ofullständigt kartlagda.



Syftet med denna avhandling var att undersöka vilken roll tumörmikromiljön har vid pankreascancer med målsättning att nå ökad förståelse om faktorer som bidrar till cancertillväxt och möjligheter att utveckla riktad behandling.



I delarbete I har vi för första gången lyckats skapa två immortaliserade humana cellinjer bestående av normala respektive tumör-associerade pankreatiska stellatceller. De pankreatiska stellatcellerna anses ha en nyckelroll i den stromala reaktionen vid pankreascancer. I denna studie fann vi att IGF-I stimulerade tillväxten av båda cellinjerna. Den cellulära motiliteten var ökad i de tumörassocierade stellatcellerna jämfört med de normala cellerna och stimulerades ytterligare av IGF-I.



I delarbete II fann vi att gurkmeja och L49H37 (en ny gurkmeja analog) hämmade tillväxten av tumör-associerade pankreatiska stellatceller och bidrog till ökade nivåer av apoptos (programmerad celldöd). De tumör-associerade pankreatiska stellatcellerna stannade i G0/G1-fasen av cellcykeln genom nedreglering av p21WAF1/Cip1. L49H37 minskade signifikant fosforyleringen av ERK1/2. Vidare fann vi att det krävdes endast en tiondel av dosen L49H37 jämfört med vanlig gurkmeja för att uppnå samma tillväxthämmande effekt.



I delarbete III studerades proteinet SPARC som anses vara involverad i tumörstroma interaktionen vid pankreascancer. Vi analyserade uttrycket av SPARC i normal pankreas, primär pankreascancer samt lymfkörtelmetastaser. Våra resultat visade att SPARC uttryck saknades i normal pankreas men att proteinet var uttryckt i pankreascancer och detta uttryck behölls i metastaserna. SPARC uttryck begränsades till de stromala cellerna. Överlevnaden av patienter med högt stromalt SPARC uttryck var betydligt sämre än för de patienter med lågt stromal SPARC uttryck (11,5 vs 25,3 månader, p = 0,020).



I delarbete IV fann vi att kombinerad behandling av sorafenib och celecoxib synergistiskt inducerade tillväxthämning och apoptos i pankreascancerceller genom en process som involverar nedreglering av p21WAF1/Cip1. (Less)
Abstract
Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths, with a 5-year survival less than 6%. It does not show any symptoms in its early stages, hence most (>85%) of the patients are diagnosed at late stage. At the time of diagnosis, metastases are frequently observed which make most patients unsuitable for curative surgical treatment and chemotherapy remains the only choice for them. In addition, PC is resistant to chemotherapy and currently available treatments provide only marginal survival benefits. PC is characterized by a dense desmoplastic (stromal) reaction surrounding the tumour cells, which is believed to promote tumour survival and chemoresistance. Although being a central pathological feature of... (More)
Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths, with a 5-year survival less than 6%. It does not show any symptoms in its early stages, hence most (>85%) of the patients are diagnosed at late stage. At the time of diagnosis, metastases are frequently observed which make most patients unsuitable for curative surgical treatment and chemotherapy remains the only choice for them. In addition, PC is resistant to chemotherapy and currently available treatments provide only marginal survival benefits. PC is characterized by a dense desmoplastic (stromal) reaction surrounding the tumour cells, which is believed to promote tumour survival and chemoresistance. Although being a central pathological feature of pancreatic cancer, the cellular and molecular interactions underlying the stromal reaction remain incompletely understood.



The aim of the thesis was to investigate the role of the tumour microenvironment in pancreatic cancer progression.



To address the role of the stroma, we have managed to generate the first conditionally immortalized human nontumour (NPSC) and tumour-derived pancreatic stellate cells (TPSC). PSCs are believed to be the principal source of the stromal reaction in PC. In our study, we have found that insulin-like growth factor-I stimulated the proliferation of both PSCs. Both basal and IGF-I stimulated motility was significantly enhanced in TPSC compared to NPSC. Further we have found that curcumin and L49H37 effectively inhibited proliferation and

induced apoptosis in TPSC. TPSC were retained in the G0/G1 phase of the cell cycle through the down-regulation of p21WAF1/Cip1. L49H37 significantly decreased the phosphorylation of ERK1/2. L49H37 was found to be more potent at a lower concentration than curcumin.



It has been stated that secreted protein acidic and rich in cysteine (SPARC) is involved in the tumour-stroma interaction. We have evaluated SPARC expression in normal pancreas, invasive adenocarcinoma and lymph node metastasis. Our data revealed that SPARC expression was absent in normal pancreas but expressed in invasive adenocarcinoma and its expression was maintained in subsequent metastases. SPARC expression was exclusively found in stromal cells. The survival of patients with high stromal SPARC expression was significantly worse than that of the patients with low stromal SPARC expression (11.5 vs 25.3 months; p = 0.020).



We observed that combined treatment of sorafenib and celecoxib synergistically induced growth inhibition and apoptosis in pancreatic cancer cells (PCC) through a process involving p21WAF1/Cip1 suppression.



This thesis provides insights into interactions and mechanisms within the pancreatic tumour microenvironment, with potential implications for targeted interventions. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Gladhaug, Ivar P, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2015:66
pages
56 pages
publisher
Surgery (Lund)
defense location
Belfragesalen, BMC D15, Klinikgatan 32, Lund
defense date
2015-05-25 13:00
ISSN
1652-8220
ISBN
978-91-7619-145-3
language
English
LU publication?
yes
id
8f4bdca8-b3a6-473f-9095-adbc6232c22e (old id 5337109)
date added to LUP
2015-04-29 09:10:45
date last changed
2016-09-19 08:44:45
@phdthesis{8f4bdca8-b3a6-473f-9095-adbc6232c22e,
  abstract     = {Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths, with a 5-year survival less than 6%. It does not show any symptoms in its early stages, hence most (&gt;85%) of the patients are diagnosed at late stage. At the time of diagnosis, metastases are frequently observed which make most patients unsuitable for curative surgical treatment and chemotherapy remains the only choice for them. In addition, PC is resistant to chemotherapy and currently available treatments provide only marginal survival benefits. PC is characterized by a dense desmoplastic (stromal) reaction surrounding the tumour cells, which is believed to promote tumour survival and chemoresistance. Although being a central pathological feature of pancreatic cancer, the cellular and molecular interactions underlying the stromal reaction remain incompletely understood.<br/><br>
<br/><br>
The aim of the thesis was to investigate the role of the tumour microenvironment in pancreatic cancer progression.<br/><br>
<br/><br>
To address the role of the stroma, we have managed to generate the first conditionally immortalized human nontumour (NPSC) and tumour-derived pancreatic stellate cells (TPSC). PSCs are believed to be the principal source of the stromal reaction in PC. In our study, we have found that insulin-like growth factor-I stimulated the proliferation of both PSCs. Both basal and IGF-I stimulated motility was significantly enhanced in TPSC compared to NPSC. Further we have found that curcumin and L49H37 effectively inhibited proliferation and<br/><br>
induced apoptosis in TPSC. TPSC were retained in the G0/G1 phase of the cell cycle through the down-regulation of p21WAF1/Cip1. L49H37 significantly decreased the phosphorylation of ERK1/2. L49H37 was found to be more potent at a lower concentration than curcumin.<br/><br>
<br/><br>
It has been stated that secreted protein acidic and rich in cysteine (SPARC) is involved in the tumour-stroma interaction. We have evaluated SPARC expression in normal pancreas, invasive adenocarcinoma and lymph node metastasis. Our data revealed that SPARC expression was absent in normal pancreas but expressed in invasive adenocarcinoma and its expression was maintained in subsequent metastases. SPARC expression was exclusively found in stromal cells. The survival of patients with high stromal SPARC expression was significantly worse than that of the patients with low stromal SPARC expression (11.5 vs 25.3 months; p = 0.020).<br/><br>
<br/><br>
We observed that combined treatment of sorafenib and celecoxib synergistically induced growth inhibition and apoptosis in pancreatic cancer cells (PCC) through a process involving p21WAF1/Cip1 suppression.<br/><br>
<br/><br>
This thesis provides insights into interactions and mechanisms within the pancreatic tumour microenvironment, with potential implications for targeted interventions.},
  author       = {Gundewar, Chinmay},
  isbn         = {978-91-7619-145-3},
  issn         = {1652-8220},
  language     = {eng},
  pages        = {56},
  publisher    = {Surgery (Lund)},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Pancreatic cancer – Influence of Tumour Microenvironment},
  volume       = {2015:66},
  year         = {2015},
}