Identification of luminal breast cancers that establish a tumor-supportive macroenvironment defined by proangiogenic platelets and bone marrow-derived cells.
Identification of luminal breast cancers that establish a tumor-supportive macroenvironment defined by proangiogenic platelets and bone marrow-derived cells.
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DOI：
10.1158/2159-8290.cd-12-0216
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发表时间：
2012-12
期刊：
影响因子：
28.2
通讯作者：
McAllister SS
中科院分区：
文献类型：
--
作者：
Kuznetsov HS;Marsh T;Markens BA;Castaño Z;Greene-Colozzi A;Hay SA;Brown VE;Richardson AL;Signoretti S;Battinelli EM;McAllister SS
乳腺癌复发率在治疗后各不相同，这表明肿瘤细胞从原发部位早期扩散，但在进展为有症状的疾病之前无限期地保持惰性。一些惰性播散性肿瘤突然转变为显性疾病的原因尚不清楚。我们发现了一个新的过程，通过该过程，某些管腔乳腺癌细胞和患者肿瘤标本（LBC“煽动者”）建立了一个支持其他惰性播散性肿瘤（“反应者”）生长的系统性宏观环境。刺激LBC分泌细胞因子，这些细胞因子被血小板吸收，血小板被募集到响应肿瘤部位，在那里它们帮助血管形成。诱导剂激活的骨髓细胞（BMC）富集了CD24（血小板的粘附分子）的响应性肿瘤细胞表达，并提供了VEGFR2+肿瘤血管细胞的来源。这种级联反应导致应答腺癌的生长，并且当血小板活化被阿司匹林抑制时被消除。这些发现强调了宏观环境作为疾病进展的重要组成部分，可以在治疗上加以利用。
Breast cancer recurrence rates vary following treatment, suggesting that tumor cells disseminate early from primary sites but remain indolent indefinitely before progressing to symptomatic disease. The reasons why some indolent disseminated tumors erupt into overt disease are unknown. We discovered a novel process by which certain luminal breast cancer cells and patient tumor specimens (LBC “instigators”) establish a systemic macroenvironment that supports outgrowth of otherwise-indolent disseminated tumors (“responders”). Instigating LBCs secrete cytokines that are absorbed by platelets, which are recruited to responding tumor sites where they aid vessel formation. Instigator-activated bone marrow cells (BMCs) enrich responding tumor cell expression of CD24, an adhesion molecule for platelets, and provide a source of VEGFR2+ tumor vessel cells. This cascade results in growth of responder adenocarcinomas and is abolished when platelet activation is inhibited by aspirin. These findings highlight the macroenvironment as an important component of disease progression that can be exploited therapeutically.