Novel animal model of soft tissue tumor due to aberrant hedgehog signaling activation in pericyte lineage
Novel animal model of soft tissue tumor due to aberrant hedgehog signaling activation in pericyte lineage
复制标题
由于周细胞谱系中异常的刺猬信号激活而产生的软组织肿瘤新动物模型
DOI：
10.1007/s00441-022-03578-0
复制
发表时间：
2022
影响因子：
3.6
通讯作者：
Kitazawa Sohei
中科院分区：
文献类型：
--
作者：
Haraguchi Ryuma;Kitazawa Riko;Kohara Yukihiro;Imai Yuuki;Kitazawa Sohei
周细胞是包围全身小血管内皮的多能细胞。这些细胞被认为在血管发育和血压调节中发挥有限的作用；然而，目前来自大量研究的证据表明动物周细胞的几个重要生物学方面。一种观点认为，周细胞也被认为是多种软组织肿瘤的潜在细胞起源。然而，周细胞肿瘤细胞起源的实验证据仍然不足，并且对其分子发病机制知之甚少。在这里，我们使用条件组成型活性平滑等位基因（Rosa-SmoM2）和Cre重组酶小鼠来激活刺猬（Hh）信号，仅在单核细胞/巨噬细胞和破骨细胞谱系（LysMcre）或被识别为破骨细胞前体细胞的RANK表达细胞（RANKcre）中。用 LysMcre 条件表达 SmoM2 的小鼠没有表现出明显的骨骼表型；然而，令人惊讶的是，RANKcre； Rosa-SmoM2 小鼠的腿部区域经常出现进行性软组织肿瘤。遗传谱系追踪分析发现骨骼肌间质细胞中表达 RANKcre 的细胞的一个新域，其显示与血管周细胞一致的标记。这些细胞产生的肿瘤显示基质金属蛋白酶（MMP）表达增加，这是恶性肿瘤的分子指标。此外，肿瘤表现出与破骨细胞骨吸收相关的强大骨侵袭能力。因此，这些发现为肿瘤病理学提供了新的见解：Hh信号激活周细胞可能是多种软组织肿瘤的潜在细胞起源。
Pericytes are pluripotent cells that enclose the endothelium of small blood vessels in the whole body. These cells are thought to play a limited role in vascular development and blood pressure regulation; however, current evidence from numerous studies suggests several significant biologic aspects of pericytes in animals. One viewpoint is that pericytes are also known as potential cellular origin of multiple soft tissue tumors. Experimental evidence of the cellular origin of pericytic tumors is still insufficient, however, and their molecular pathogenesis is poorly understood. Here, we used a conditional constitutively active Smoothened allele (Rosa-SmoM2) and Cre recombinase mice to activate hedgehog (Hh) signaling, exclusively in the monocyte/macrophage and osteoclast lineage (LysMcre) or in RANK expressing cells (RANKcre) that are recognized as osteoclast precursor cells. Mice conditionally expressing SmoM2 with LysMcre displayed no significant skeletal phenotype; surprisingly, however, RANKcre; Rosa-SmoM2 mice frequently developed progressive soft tissue tumors in regions of the leg. Genetic lineage tracing analysis uncovered a new domain of RANKcre-expressing cells in the skeletal muscle interstitial cells that display markers consistent with vascular pericytes. Neoplasms arising from these cells showed increased expression of Matrix metalloproteinases (MMPs) that are molecular indicators of malignancy. Moreover, the tumors displayed strong bone invasive potency associated with osteoclastic bone resorption. Thus, these findings provide a novel insight into tumor pathology: Hh signal activated-pericytes can be a potential cellular origin of multiple soft tissue tumors.
登录
查看更多内容
影响因子：
50.3
作者：
Drummond CJ;Hanna JA;Garcia MR;Devine DJ;Heyrana AJ;Finkelstein D;Rehg JE;Hatley ME
通讯作者：
Hatley ME
PP2Cβ和PP2Cε在RANKL/RANK信号通路中的作用
DOI：
--
发表时间：
2007
期刊：
影响因子：
--
作者：
Harata M. ;et. al.;Nakagawa H 他;Yonezawa T 他;Harata M;大西 素子;原田昌彦;Motoko Ohnishi;Harata et al.;大西素子 他;Notoya M 他;Woo JT 他;藤澤 望美;吉田 真実;Nozomi Fujisawa;Mami Yoshida;吉田真実;Nobuhiro Aburai;Nobuhiro Aburai;Nobuhiro Aburai;大西 素子;Motoko Ohnishi;大西素子;油井 信弘;三好 信寛
通讯作者：
三好 信寛
影响因子：
50.3
作者：
Hatley ME;Tang W;Garcia MR;Finkelstein D;Millay DP;Liu N;Graff J;Galindo RL;Olson EN
通讯作者：
Olson EN
影响因子：
5.6
作者：
Folpe, AL;Fanburg-Smith, JC;Weiss, SW
通讯作者：
Weiss, SW
影响因子：
20.3
作者：
Stratman, Amber N.;Malotte, Kristine M.;Davis, George E.
通讯作者：
Davis, George E.