Abstrakti
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. Options for treatment are limited, and the only possibility of cure is radical surgery combined with chemotherapy. Inflammation and tumor stroma are important mediators in PDAC progression. Tumor-associated macrophages (TAMs), among other cells, create an immunosuppressive microenvironment and enhance tumor progression. Because they pivotally participate in tumorigenesis, TAMs are a potential target for therapeutic intervention. The aim of these studies was to explore inflammation and TAMs in PDAC. Three of the studies were conducted in cell cultures, and one was a retrospective clinical study. We polarized macrophages in cell cultures towards inflammatory M1 and anti-inflammatory M2 phenotypes and assessed the changes in the signaling pathways and the effect they had on pancreatic cancer cell migration. We studied the association of preoperative systemic inflammatory response (SIR), based on laboratory data, with the outcome of 265 patients with resectable PDAC. Tumor-associated anti-inflammatory M2 macrophages promoted pancreatic cancer cell migration in co-cultures by activating their MMP9 and ADAM8 expression. Support of the pro-inflammatory M1 phenotype causes these macrophages to inhibit cancer cell migration. Several intracellular STAT pathways and the NFkB pathway were activated by the interactions of cancer cells and macrophages. In preoperative laboratory data, patients elevated C-reactive protein (CRP), an indicator of SIR, predicted worse postoperative survival. Moreover, low levels of albumin, the most abundant protein in human blood circulation, as well as elevated tumor markers CA19-9 and CEA, were associated with worse survival. These studies provide novel insight into the interaction of TAMs and PDAC. The results encourage further research into TAMs and exploration of the possibilities of skewing macrophage polarization toward the inflammatory M1 phenotype. Development of SIR seems detrimental for patients with PDAC and predicts worse outcome. Preoperative CRP, in combination with albumin and tumor markers and clinical data, could prove useful when evaluating patients prognosis.
Alkuperäiskieli | englanti |
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Valvoja/neuvonantaja |
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Julkaisupaikka | Helsinki |
Kustantaja | |
Painoksen ISBN | 978-951-51-2955-0 |
Sähköinen ISBN | 978-951-51-2956-7 |
Tila | Julkaistu - 2017 |
OKM-julkaisutyyppi | G5 Tohtorinväitöskirja (artikkeli) |
Lisätietoja
M1 - 102 s. + liitteetTieteenalat
- ADAM Proteins
- Adenocarcinoma
- +immunology
- +pathology
- Biomarkers, Tumor
- C-Reactive Protein
- Carcinoma, Pancreatic Ductal
- Cell Movement
- Cells, Cultured
- Gene Expression Regulation, Neoplastic
- Macrophages
- +metabolism
- Matrix Metalloproteinase 9
- Membrane Proteins
- Neoplasm Invasiveness
- Pancreatic Neoplasms
- Prognosis
- STAT3 Transcription Factor
- Systemic Inflammatory Response Syndrome
- 3122 Syöpätaudit
- 3126 Kirurgia, anestesiologia, tehohoito, radiologia