Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression
Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression
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DOI：
10.1016/j.canlet.2021.04.013
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发表时间：
2021-05-10
期刊：
影响因子：
9.7
通讯作者：
Nakamura, Masafumi
中科院分区：
文献类型：
--
作者：
Iwamoto, Chika;Ohuchida, Kenoki;Nakamura, Masafumi
胰腺导管腺癌（PDAC）的特征在于由癌症相关成纤维细胞（CAF）引起的促纤维增生反应，其引起治疗抗性。CAFs是新近提出的在PDAC微环境中具有不同功能的异质种群。CAF最直接的来源是常驻组织成纤维细胞和间充质干细胞，然而，CAF亚型的起源和功能尚不清楚。在这里，我们使用自发性PDAC小鼠建立了异基因骨髓（BM）移植模型，然后研究来自BM的哪些亚型细胞调节肿瘤微环境并影响胰腺癌细胞（PCCs）的行为。骨髓来源的多系造血细胞移植到受体胰腺，并在PDAC的侵袭性前部和中央病变处聚集。我们在肿瘤中鉴定了BM巨噬细胞来源的CAF。用PCC条件培养基处理的BM衍生的巨噬细胞表达CAF标志物。骨髓源性巨噬细胞在体外可诱导PCCs局部侵袭，在体内可促进肿瘤的侵袭性生长。我们的数据表明，BM衍生的细胞在癌变过程中被招募到胰腺，并且BM衍生的巨噬细胞的特定亚群部分转化为CAF样细胞，充当主导细胞，并促进胰腺癌的进展。控制BM源性巨噬细胞向CAF样细胞的转化可能是抑制肿瘤生长的一种新的治疗策略。
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic reaction caused by cancer associated fibroblasts (CAFs), which provokes treatment resistance. CAFs are newly proposed to be heterogeneous populations with different functions within the PDAC microenvironment. The most direct sources of CAFs are resident tissue fibroblasts and mesenchymal stem cells, however, the origins and functions of CAF subtypes remain unclear. Here, we established allogeneic bone marrow (BM) transplantation models using spontaneous PDAC mice, and then investigated what subtype cells derived from BM modulate the tumor microenvironment and affect the behavior of pancreatic cancer cells (PCCs). BM-derived multilineage hematopoietic cells were engrafted in recipient pancreas, and accumulated at the invasive front and central lesion of PDAC. We identified BM macrophages-derived CAFs in tumors. BM-derived macrophages treated with PCC-conditioned media expressed CAF markers. BM-derived macrophages led the local invasion of PCCs in vitro and enhanced the tumor invasive growth in vivo. Our data suggest that BM-derived cells are recruited to the pancreas during carcinogenesis and that the specific subpopulation of BM-derived macrophages partially converted into CAF-like cells, acted as leading cells, and facilitated pancreatic cancer progression. The control of the conversion of BM-derived macrophages into CAF-like cells may be a novel therapeutic strategy to suppress tumor growth.