The molecular mechanism of gastric cancer cells proliferation through immune response by tumor-associated macrophages (TAMs)

  • 林 長霓

Student thesis: Doctoral Thesis

Abstract

Gastric cancer is the fourth most commonly diagnosed cancer and is also the second leading cause of cancer related deaths worldwide Asia is the highest incidence region Some risk factors contribute to gastric carcinogenesis such as diet tobacco Helicobacter pylori infection and chronic inflammation Clinical evidence indicates inflammation frequently manifested in gastric cancer The infiltrating inflammatory cells of tumor area are called the tumor-associated macrophages (TAMs) or called type II macrophages (M2-TAMs) The interplay of gastric cancer cells and TAMs in the tumor microenvironment is crucial for cancer progression Many studies have confirmed tumor cells can secrete recruitment molecules to recruit and educate circulating monocyte skew it toward M2-TAMs and these M2-TAMs can promote tumor progression But the molecular mechanism of cancer cell promotes M2-TAMs formation is still unclear Osteopontin (OPN) is a secreted type of extracellular matrix protein and it possesses an ability of macrophage recruitment OPN can activate downstream signals via binding with surface receptor like CD44 or Integrin ?vβ3 Recently some studies found OPN contribution in tumor growth angiogenesis and metastasis We also noticed OPN expression in gastric cancer specimens were associated with the quantity of infiltrating M2-TAMs The coexpression of OPN and CD204 were also associated with poor outcome We demonstrated paracrine regulation is existed between gastric cancer cell and M2-TAMs Hence we used the trans-well chamber to separate human gastric cancer cells (AGS AZ521) and human monocytic cells (U937 THP-1) to mimic a inflammatory microenvironment The gastric cancer cell-secreted OPN can interact with the U937 surface receptor ITGAL to promote the M2-TAMs formation The OPN-ITGAL axis promotes the ERK/NFκB signal activation to produce TNF-? And then the TAM-derived TNF-? acting on TNFR of gastric cancer cell to promote tumor progression In animal experiments we successfully induced proximity 60% Xenografts grew through AGS and M2-TAMs co-injected into nude mice But inhibition of OPN ITGAL or TNF/TNFR signal activation can reduce the tumor development In clinical specimens the expression of TNFR in gastric tumor is more than normal epithelium Thus the loop of gastric cancer cell-secreted OPN M2-TAMs and TNFR signal may be the important target in future therapy We also assess the feasibility of TNF inhibitor and 5-Fu combined therapy in mice and found the tumor inhibition efficiency for combined therapy is better than 5-Fu or adalimumab (TNF monoclonal antibody) alone Consequently this study demonstrated gastric cancer cell-secreted OPN promote the M2-TAMs formation through interacting with the functional receptor ITGAL to activate ERK/NFκB signal and produce TNF-? And then the TAM-derived TNF-? promotes gastric cancer progression through TNFR signal activation The tumor progression can be reduced through inhibit the M2-TAMs formation and block the TNFR activation 5-Fu combined with and TNF-? inhibition is also an effective adjuvant therapy Thus blocking the gastric cancer cell-derived OPN-ITGAL axis or inhibiting TNFR signal activation is the potential target in future therapy
Date of Award2015 Jun 25
Original languageEnglish
SupervisorYan-Shen Shan (Supervisor)

Cite this

The molecular mechanism of gastric cancer cells proliferation through immune response by tumor-associated macrophages (TAMs)
長霓, 林. (Author). 2015 Jun 25

Student thesis: Doctoral Thesis