Inflammation leads to loss of smooth muscle cells but fails to induce invasiveness in a prostate tumor model

Inflammation has a causal role in many cancers. In prostate cancers, epidemiological data suggest a link between prostatitis and subsequent cancer development, but a proof for this concept in a tumor model has been lacking. A constitutively active version of the IkappaB kinase 2 (IKK2), the molecule activated by a plethora of inflammatory stimuli, was expressed specifically in the prostate epithelium. Signaling of the IKK2/NF-kappaB axis was insufficient for transformation of prostate tissue. However, while PTEN+/- epithelia exhibited intraepithelial neoplasias only recognizable by nuclear alterations, additional IKK2 activation led to an increase in tumor size and formation of cribriform structures and to a fiber increase in the fibroblastic stroma. This phenotype was coupled with inflammation in the prostate gland characterized by infiltration of granulocytes and macrophages. Molecular characterization of the tissues showed a specific loss of smooth muscle markers as well as expression of chemokines attracting immune cells. Isolation of epithelial and stromal cells showed differential chemokine expression by these cells. Correlation studies showed the inflammatory phenotype coupled to loss of smooth muscle in infiltrated glands, but maintenance of the phenotype in glands where inflammation had decreased. Despite the loss of the smooth muscle barrier, tumors were not invasive in a stable genetic background. Data mining revealed that smooth muscle markers are downregulated in human prostate cancers and literature data show that loss of these markers in primary tumors is associated with subsequent metastasis. Our data show that loss of smooth muscle and invasiveness of the tumor are not coupled. Thus, inflammation during early steps of tumorigenesis can lead to increased tumor size and a potential change in the subsequent metastatic potential, but the tumor requires an additional transformation to become a carcinoma. Microarray analysis was used to determine expression differences in lateral prostates from mice with PTEN+/- IKK2ca/ca epithelium (n=3) compared to lateral prostates from mice with PTEN+/- epithelium (n=3).

炎症在多种癌症中均具有致病作用。针对前列腺癌，流行病学数据提示前列腺炎与后续癌症发生存在关联，但目前仍缺乏肿瘤模型层面的该假说验证依据。研究中将由大量炎症刺激激活的κB抑制蛋白激酶2（IkappaB kinase 2, IKK2）的组成型激活变体特异性表达于前列腺上皮细胞中。IKK2/核因子κB（NF-κB）信号轴的转导不足以诱导前列腺组织发生恶性转化。然而，尽管磷酸酶与张力蛋白同源物（PTEN）杂合缺失的上皮细胞仅表现出可通过核形态改变识别的上皮内瘤变，但额外的IKK2激活可促使肿瘤体积增大、形成筛状结构，并增加成纤维细胞基质中的纤维成分。该表型伴随前列腺炎症反应，特征为粒细胞与巨噬细胞浸润。对组织的分子表征分析显示，平滑肌标志物特异性缺失，同时表达可招募免疫细胞的趋化因子。上皮细胞与基质细胞的分离实验表明，两类细胞的趋化因子表达存在差异。相关性研究显示，炎症表型与浸润腺体中平滑肌标志物的缺失相关，但在炎症已消退的腺体中则保留原有表型。尽管平滑肌屏障遭到破坏，但在稳定的遗传背景下，肿瘤并未发生侵袭。数据挖掘结果显示，人类前列腺癌中平滑肌标志物表达下调，且已有文献表明，原发肿瘤中此类标志物的缺失与后续肿瘤转移相关。本研究数据表明，平滑肌标志物缺失与肿瘤侵袭性并无关联。因此，肿瘤发生早期阶段的炎症反应可导致肿瘤体积增大，并可能改变后续转移潜能，但肿瘤仍需额外的转化事件才能发展为侵袭性癌。本研究采用微阵列分析，对比了PTEN杂合缺失且上皮细胞表达组成型激活IKK2的小鼠（n=3）与仅PTEN杂合缺失的小鼠（n=3）的外侧前列腺组织的基因表达差异。