Analysis of tumor-associated neutrophils at the invasive front of submucosal invasive colorectal cancer

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17057
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Sudo Gota 札幌医科大学, 医学部, 訪問研究員 (60830130)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 大腸がん / 粘膜下層浸潤 / 腫瘍微小環境 / サイトカイン / MMP9

Outline of Final Research Achievements

Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). We identified that serum amyloid A1 (SAA1) was specifically expressed in poorly differentiated regions (PORs) at the invasive front of T1 CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. Co-culture experiments suggested that interleukin 1β (IL-1β) produced by macrophages induces SAA1 expression in CRC cells. These findings were supported by immunohistochemical analysis of primary T1 CRCs showing accumulation of macrophages and neutrophils at SAA1-positive invasive front regions. SAA1 produced by CRC cells stimulated upregulation of MMP9 in macrophages and neutrophils. Our data suggest that tumor-associated macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1, and that SAA1 may be a predictive biomarker and a therapeutic target.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

大腸粘膜下層浸潤がん(SMがん)の約90%はリンパ節転移がなく、低侵襲な内視鏡治療により根治切除が可能である。しかし、現行の転移リスク層別化基準に従って、内視鏡治療後に追加外科手術を行ったSMがん症例の約90%が過剰な外科治療となっている。我々は浸潤先進部の低分化成分・簇出において、SAA1が特異的に高発現することを見いだした。さらに免疫組織染色解析から結果、SAA1高発現領域の周囲にマクロファージと好中球が有意に集簇すること、これらがSSA1刺激によりMMP9を産生することを明らかにした。本研究から、SAA1が浸潤・転移予測マーカーや治療標的として有用性である可能性が示された。