Cancer-associated stroma fibroblasts promote pancreatic tumor progression
Cancer-associated stroma fibroblasts promote pancreatic tumor progression
复制标题
DOI：
10.1158/0008-5472.can-07-5714
复制
发表时间：
2008-02-01
期刊：
影响因子：
11.2
通讯作者：
Logsdon, Craig D.
中科院分区：
文献类型：
--
作者：
Hwang, Rosa F.;Moore, Todd;Logsdon, Craig D.
胰腺腺癌的特征是肿瘤相关基质的致密背景，其起源于丰富的胰腺星状细胞。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。从切除的胰腺癌样品中分离HPSC，并用端粒酶和SV 40大T抗原使其永生化。在两种胰腺癌细胞系中测定了HPSC条件培养基（HPSC-CM）对体外增殖、迁移、侵袭、软琼脂集落形成和在吉西他滨或放射治疗存在下的存活的影响。通过将RPSC与癌细胞共注射并分析生长和转移，在原位胰腺癌小鼠模型中检查RPSC对肿瘤的作用。HPSC-CM剂量依赖性地增加BxPC 3和Panel肿瘤细胞增殖、迁移、侵袭和集落形成。此外，吉西他滨和放射疗法在用HPSC-CM处理的肿瘤细胞中效果较差。HPSC-CM激活肿瘤细胞中的丝裂原活化蛋白激酶和Akt通路。在原位模型中，肿瘤细胞与HPSC的共注射导致原发性肿瘤发生率、大小和转移增加，这与RPSC的比例相对应。HPSC产生可溶性因子，刺激与胰腺癌细胞增殖和生存相关的信号通路，并且肿瘤中HPSC的存在会增加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中具有重要作用。HPSC衍生因子的鉴定可能导致胰腺癌的新型基质靶向治疗。
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 RPSCs 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 Panel 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 RPSCs. 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.