Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Clin Cancer Res. 2011 Nov 15;17(22):7015-23. doi: 10.1158/1078-0432.CCR-11-0607. Epub 2011 Oct 5.
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death. No effective therapy is currently available for PDAC because of the lack of understanding of the mechanisms leading to its growth and development. Inflammatory cells, particularly mast cells, have been shown to play key roles in some cancers. We carried out this study to test the hypothesis that mast cells in the tumor microenvironment are essential for PDAC tumorigenesis.
The presence of inflammatory cells at various stages of PDAC development was determined in a spontaneous mouse model of PDAC (K-ras(G12V)). The importance of mast cells was determined using orthotopically implanted PDAC cells in mast cell-deficient Kit(w-sh/w-sh) mice and further confirmed by reconstitution of wild-type bone marrow-derived mast cells. Clinical relevance was assessed by correlating the presence of mast cells with clinical outcome in patients with PDAC.
In the spontaneous mouse model of PDAC (K-ras(G12V)), there was an early influx of mast cells to the tumor microenvironment. PDAC tumor growth was suppressed in mast cell-deficient Kit(w-sh/w-sh) mice, but aggressive PDAC growth was restored when PDAC cells were injected into mast cell-deficient mice reconstituted with wild-type bone marrow-derived mast cells. Mast cell infiltration into the tumor microenvironment was predictive of poor prognosis in patients with PDAC.
Mast cells play an important role in PDAC growth and development in mouse models and are indicative of poor prognosis in humans, which makes them a potential novel therapeutic target.
胰腺导管腺癌（PDAC）是癌症死亡的主要原因之一。由于缺乏对导致其生长和发展的机制的理解，目前尚无有效的治疗方法。炎性细胞，特别是肥大细胞，已被证明在某些癌症中发挥关键作用。我们进行这项研究是为了检验这样一个假设，即在肿瘤微环境中的肥大细胞对于 PDAC 的肿瘤发生是必不可少的。
在自发性 PDAC 小鼠模型（K-ras(G12V)）中，在 PDAC 发展的各个阶段确定炎性细胞的存在。使用在肥大细胞缺陷型 Kit(w-sh/w-sh)小鼠中植入的原位 PDAC 细胞和进一步通过野生型骨髓衍生的肥大细胞的重建来确定肥大细胞的重要性。通过将肥大细胞的存在与 PDAC 患者的临床结果相关联来评估临床相关性。
在自发性 PDAC 小鼠模型（K-ras(G12V)）中，肥大细胞早期涌入肿瘤微环境。在肥大细胞缺陷型 Kit(w-sh/w-sh)小鼠中，PDAC 肿瘤生长受到抑制，但当将 PDAC 细胞注入用野生型骨髓衍生的肥大细胞重建的肥大细胞缺陷型小鼠中时，侵袭性 PDAC 生长得到恢复。肥大细胞浸润肿瘤微环境预示着 PDAC 患者预后不良。
肥大细胞在小鼠模型中 PDAC 的生长和发展中发挥重要作用，并且在人类中预示着预后不良，这使其成为一个潜在的新的治疗靶点。
