Anti-tumorigenic Effects of Naive and TLR4-Primed Adipose-Derived Mesenchymal Stem Cells on Pancreatic Ductal Adenocarcinoma Cells

Kaçaroğlu D., Yaylacı S., Gürbüz N.

CANCER MEDICINE, sa.January, ss.1-40, 2024 (SCI-Expanded)

  • Yayın Türü: Makale / Tam Makale
  • Basım Tarihi: 2024
  • Doi Numarası: 10.1002/cam4.6964
  • Dergi Adı: CANCER MEDICINE
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, EMBASE, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Sayfa Sayıları: ss.1-40
  • Lokman Hekim Üniversitesi Adresli: Evet

Özet

One of the main reasons for the unsuccessful treatment of pancreatic

cancer is the intense desmoplastic pancreatic microenvironment. In the

literature, the effects of Mesenchymal Stem Cells (MSCs) and their

inflammatory phenotypes on cancer cells have been a subject of

controversy. Therefore, it is crucial to elucidate the underlying

mechanisms of this interaction, especially in the context of pancreatic

cancer. We aimed to investigate the effects of naive, TLR4-activated, and

TLR4-inhibited phenotypes of adipose-derived MSCs(ADMSC) on

pancreatic ductal cell line(Panc-1). ADMSCs were induced into a

proinflammatory phenotype using a 0.5 μg/ml dose of TLR4 agonist,

while an anti-inflammatory phenotype was generated in ADMSCs using a

25 μg/ml dose of TLR4 antagonist. We observed a 10 fold higher

antiproliferative effect in direct coculture of naive and proinflammatory

ADMSCs compared to Panc-1. In indirect coculture, both naive and

proinflammatory ADMSCs exhibited a significant 10-fold increase in their

inhibitory effect on the proliferation and colony forming capacity of Panc-

1 cells, with the added benefit of inducing apoptosis. In our study, both

naive and proinflammatory ADMSCs were found to regulate the

expression of genes associated with metastasis(MMP2, KDR, MMP9,

TIMP1, IGF2R, and COL1A1) and EMT(CDH1, VIM, ZEB1, and CLDN1) in

Panc-1 cells. Remarkably, both naive and proinflammatory ADMSCs

demonstrated antitumor effects on Panc-1 cells. However, it was

observed that anti-inflammatory ADMSCs showed tumor-promoting

effects instead. Furthermore, we observed a reciprocal influence between

ADMSCs and Panc-1 cells on each other's proinflammatory cytokine

expressions, suggesting a dynamic interplay within the tumor

microenvironment. These findings underscore the significance of both the naive state and different inflammatory phenotypes of MSCs in the

microenvironment and represent a pivotal step towards the development

of novel therapeutic approaches for pancreatic cancer. Understanding

the intricate interactions between MSCs and cancer cells may open new

avenues for targeted interventions in cancer therapy.