Exosomes in tumor cell-mesenchymal stromal cell interaction

摘要 骨髓是一种异质器官，在癌症的发展和转移中起着中心作用。 它构成了播散性肿瘤细胞的利基，保护它们免受治疗，促进它们的休眠和 使它们能够转移到其他器官。癌细胞驻扎并劫持BM利基，将其转化为 恶性生态位有利于肿瘤细胞的增殖和存活。因此，研究肿瘤之间的串扰 细胞和BM的微环境是一个很有兴趣的课题。我们实验室的一项主要工作是 研究癌细胞与骨髓间充质基质细胞(BM-MSC)的通讯 形成了BM-生态位，我们已经证明对促癌肿瘤微环境(TME)有贡献。 我们关注神经母细胞瘤(NB)，这是一种源于神经脊部的肿瘤，是世界上第二常见的实体瘤 儿童，而且经常和特异性地转移到骨和骨髓以及肿瘤外体上。 这些细胞外小泡(EV)已经成为一种新的、强大的沟通机制 肿瘤细胞及其环境通过其传递多分子生物学信息的能力 比单一增长因素更复杂。本申请中的初步数据表明，NB细胞 释放BM-捕获的富含Syntenin、Alix、Tetraspanin CD-63和Gal-3BP的外体 MSC和一种促肿瘤的炎症反应。我们最重要的假设是，由于他们的 MSC，Nb衍生的外切体激活BM生态位，促进Nb的归巢和生存 骨髓中的细胞。我们特别假设Syntenin在它们的生物发生和 Gal-3BP通过与BM-MSC表面的蛋白质相互作用来控制它们的摄取。在第一个目标中 我们将确定Nb来源的外切体对转移前BM生态位的贡献及其贡献 将药理学和遗传学结合起来(敲除和敲除) 人骨髓间充质干细胞体外培养及转移和非转移NB细胞体内研究进展 台词。在目标2中，我们将在BM-MSC中鉴定与Gal-3BP相互作用的蛋白质(S)。 与纽约康奈尔大学的David Lyden博士合作，在MSC中摄取外切体，比较 不同BM嗜性的NB和乳腺癌细胞系外切体被BM-MSC和BM摄取 造血干细胞(HSC)主要摄取Gal-3BP和整合素。这些研究将提供 外切体参与肿瘤细胞与细胞间通讯机制的新认识 BM利基市场。预计这些研究最终将确定干预或预防艾滋病的目标。 癌症转移。

ABSTRACT The bone marrow (BM) is a heterogeneous organ with a central function in cancer progression and metastasis. It constitutes a niche for disseminated tumor cells, protecting them from therapy, promoting their dormancy and allowing them to metastasize to other organs. Cancer cells home to and hijack the BM niche converting it to a malignant niche favorable to tumor cell proliferation and survival. Thus, studying the cross-talk between tumor cells and the BM microenvironment is a subject of high interest. A major effort of our laboratory has been to study the communication between cancer cells and BM-derived mesenchymal stromal cells (BM-MSC) that form the BM-niche and that we have shown to contribute to a protumorigenic tumor microenvironment (TME). We focus on neuroblastoma (NB), a neural crest-derived tumor that is the second most common solid tumor in children, and that frequently and specifically metastasizes to the bone and BM and on tumor exosomes. These extracellular vesicles (EV) have emerged as a new and powerful mechanism of communication between tumor cells and their environment through their ability to convey multi-molecular biological messages of a much higher complexity than single growth factors. Preliminary data in this application demonstrate that NB cells release exosomes enriched in syntenin, ALIX, the tetraspanin CD-63 and Gal-3BP which are captured by BM- MSC and a pros-tumorigenic inflammatory reaction. Our overarching hypothesis is that as a result of their activity on MSC, NB-derived exosomes prime the BM niche, promoting the homing and survival of NB cells in the BM. We specifically hypothesize that syntenin plays a central role in their biogenesis and that Gal-3BP controls their uptake by interacting with a protein at the surface of BM-MSC. In a first aim we will determine the contribution of NB-derived exosomes to the pre-metastatic BM niche and the contribution of syntenin to their biogenesis, combining pharmacological and genetic (knock down and knock out) approaches in vitro in cultures of patient-derived MSC and in vivo in metastatic and non-metastatic NB cell lines. In aim 2, we will identify in BM-MSC the protein(s) interacting with Gal-3BP that contribute(s) to the uptake of exosomes in MSC, and in collaboration with Dr. David Lyden (Cornell University, NY), compare exosomes from NB and breast cancer cell lines that differ in BM tropism for their uptake by BM-MSC and BM hematopoietic stem cells (HSC) focusing on Gal-3BP and integrin in their uptake. These studies will provide novel insight into mechanisms by which exosomes are involved in the communication between tumor cells and the BM niche. It is anticipated that these studies will ultimately identify targets for intervention or prevention of cancer metastasis.