The melanoma brain metastatic microenvironment: aldolase C partakes in shaping the malignant phenotype of melanoma cells - a case of inter-tumor heterogeneity.
The melanoma brain metastatic microenvironment: aldolase C partakes in shaping the malignant phenotype of melanoma cells - a case of inter-tumor heterogeneity.
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DOI：
10.1002/1878-0261.12872
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发表时间：
2021-05
影响因子：
6.6
通讯作者：
Witz IP
中科院分区：
文献类型：
--
作者：
Izraely S;Ben-Menachem S;Sagi-Assif O;Meshel T;Malka S;Telerman A;Bustos MA;Ramos RI;Pasmanik-Chor M;Hoon DSB;Witz IP
黑色素瘤-小胶质细胞串扰上调了来自几名患者的黑色素瘤细胞中的醛缩酶C（ALDOC）的表达。来自2个不同患者的黑素瘤细胞对ALDOC上调的反应是完全不同的。尽管在一种黑色素瘤细胞系（Mel 1）中增强了几种转移相关功能（包括脑转移形成），但这些功能在另一种黑色素瘤细胞系（Mel 2）中减弱。 先前的研究表明，小胶质细胞上调黑素瘤细胞中的醛缩酶C（ALDOC）的表达。本研究使用来自三种人类黑色素瘤的脑转移变体探索ALDOC在黑色素瘤脑转移（MBM）的形成和维持中的功能作用。ALDOC过表达对这三种变异体的恶性表型有不同的影响。在第一种变体中，ALDOC过表达促进细胞活力，粘附和穿越脑内皮细胞层，并扩大脑微转移形成。这种MBM变体和小胶质细胞之间的相互作用促进了后者细胞的增殖和迁移。与此形成鲜明对比的是，第二种脑转移性黑色素瘤变体中的ALDOC过表达减少或不影响相同的恶性肿瘤特征。在第三种黑色素瘤变体中，ALDOC过表达增强了恶性肿瘤的某些特征并降低了其他特征。对ALDOC过表达变体中的生物学功能和疾病途径的分析清楚地表明，ALDOC在第一变体中诱导肿瘤进展促进基因的表达，在第二变体中诱导抗肿瘤进展特性。总的来说，这些结果强调了小胶质细胞和MBM之间复杂的微环境相互作用，以及肿瘤间异质性的功能影响。由于肿瘤间的异质性给癌症治疗的规划带来了挑战，我们建议采用具有相同组织学的肿瘤对特定药物的功能反应或这种反应的分子特征，作为对这种药物的反应/无反应的预测指标。
The melanoma‐microglia cross‐talk upregulates the expression of aldolase C (ALDOC) in melanoma cells from several patients. The response of melanoma cells from 2 different patients to ALDOC upregulation was diametrically divergent. Whereas several metastasis‐associated functions including brain metastasis formation were augmented in one melanoma cell line (Mel 1), these functions were attenuated in the other melanoma cell line (Mel 2). Previous studies indicated that microglia cells upregulate the expression of aldolase C (ALDOC) in melanoma cells. The present study using brain‐metastasizing variants from three human melanomas explores the functional role of ALDOC in the formation and maintenance of melanoma brain metastasis (MBM). ALDOC overexpression impacted differentially the malignant phenotype of these three variants. In the first variant, ALDOC overexpression promoted cell viability, adhesion to and transmigration through a layer of brain endothelial cells, and amplified brain micrometastasis formation. The cross‐talk between this MBM variant and microglia cells promoted the proliferation and migration of the latter cells. In sharp contrast, ALDOC overexpression in the second brain‐metastasizing melanoma variant reduced or did not affect the same malignancy features. In the third melanoma variant, ALDOC overexpression augmented certain characteristics of malignancy and reduced others. The analysis of biological functions and disease pathways in the ALDOC overexpressing variants clearly indicated that ALDOC induced the expression of tumor progression promoting genes in the first variant and antitumor progression properties in the second variant. Overall, these results accentuate the complex microenvironment interactions between microglia cells and MBM, and the functional impact of intertumor heterogeneity. Since intertumor heterogeneity imposes a challenge in the planning of cancer treatment, we propose to employ the functional response of tumors with an identical histology, to a particular drug or the molecular signature of this response, as a predictive indicator of response/nonresponse to this drug.
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影响因子：
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通讯作者：
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影响因子：
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