Hwang Rosa F, Moore Todd, Arumugam Thiruvengadam, Ramachandran Vijaya, Amos Keith D, Rivera Armando, Ji Baoan, Evans Douglas B, Logsdon Craig D
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77230-1402, USA.
Cancer Res. 2008 Feb 1;68(3):918-26. doi: 10.1158/0008-5472.CAN-07-5714.
Pancreatic adenocarcinoma is characterized by a dense background of tumor associated stroma originating from abundant pancreatic stellate cells. The aim of this study was to determine the effect of human pancreatic stellate cells (HPSC) on pancreatic tumor progression. HPSCs were isolated from resected pancreatic adenocarcinoma samples and immortalized with telomerase and SV40 large T antigen. Effects of HPSC conditioned medium (HPSC-CM) on in vitro proliferation, migration, invasion, soft-agar colony formation, and survival in the presence of gemcitabine or radiation therapy were measured in two pancreatic cancer cell lines. The effects of HPSCs on tumors were examined in an orthotopic murine model of pancreatic cancer by co-injecting them with cancer cells and analyzing growth and metastasis. HPSC-CM dose-dependently increased BxPC3 and Panc1 tumor cell proliferation, migration, invasion, and colony formation. Furthermore, gemcitabine and radiation therapy were less effective in tumor cells treated with HPSC-CM. HPSC-CM activated the mitogen-activated protein kinase and Akt pathways in tumor cells. Co-injection of tumor cells with HPSCs in an orthotopic model resulted in increased primary tumor incidence, size, and metastasis, which corresponded with the proportion of HPSCs. HPSCs produce soluble factors that stimulate signaling pathways related to proliferation and survival of pancreatic cancer cells, and the presence of HPSCs in tumors increases the growth and metastasis of these cells. These data indicate that stellate cells have an important role in supporting and promoting pancreatic cancer. Identification of HPSC-derived factors may lead to novel stroma-targeted therapies for pancreatic cancer.
胰腺腺癌的特征是存在由大量胰腺星状细胞产生的致密肿瘤相关基质背景。本研究的目的是确定人胰腺星状细胞（HPSC）对胰腺肿瘤进展的影响。从切除的胰腺腺癌样本中分离出HPSC，并通过端粒酶和SV40大T抗原使其永生化。在两种胰腺癌细胞系中测量了HPSC条件培养基（HPSC-CM）对体外增殖、迁移、侵袭、软琼脂集落形成以及在吉西他滨或放射治疗存在下的存活的影响。通过将HPSC与癌细胞共注射并分析生长和转移，在胰腺癌的原位小鼠模型中研究了HPSC对肿瘤的影响。HPSC-CM剂量依赖性地增加了BxPC3和Panc1肿瘤细胞的增殖、迁移、侵袭和集落形成。此外，吉西他滨和放射治疗对用HPSC-CM处理的肿瘤细胞效果较差。HPSC-CM激活了肿瘤细胞中的丝裂原活化蛋白激酶和Akt信号通路。在原位模型中将肿瘤细胞与HPSC共注射导致原发性肿瘤的发生率、大小和转移增加，这与HPSC的比例相对应。HPSC产生可溶因子，刺激与胰腺癌细胞增殖和存活相关的信号通路，并且肿瘤中HPSC的存在增加了这些细胞的生长和转移。这些数据表明星状细胞在支持和促进胰腺癌方面具有重要作用。鉴定HPSC衍生的因子可能会导致针对胰腺癌的新型基质靶向治疗方法。
