10月23日，来自宾夕法尼亚大学的研究人员在Cell上发表了关于exosome从基质细胞转移到乳腺癌细胞从而调节其治疗的耐受性通路的最新研究成果。
该研究发现，基质细胞和乳腺癌细胞利用旁分泌（paracrine）和近分泌（juxtacrine）信号来启动化疗和放疗的耐受性。在这中复杂的相互作用中，exosome从基质细胞转移到乳腺癌细胞。Exosome中的RNA成分，大部分是非编码转录本和可转移元件，促进RIG-I受体的识别，从而激活STAT1依赖的抗病毒信号通路。与此同时，基质细胞也能激活乳腺癌细胞的NOTCH3。这种旁分泌的抗病毒作用和近分泌NOTCH3信号通路在STAT1汇合从而促进NOTCH3的转录反应和治疗耐受的肿瘤起始细胞的繁殖。初始的人/鼠乳腺癌细胞分析支持antiviral/NOTCH3信号在NOTCH信号通路和基质介导的耐受中的作用，这种作用能被gamma分泌酶抑制剂废除。因此，基质细胞利用exosome来介导抗病毒信号参与了一个错综复杂的与乳腺癌细胞的相互作用。这能够使乳腺癌耐受治疗并重新起始肿瘤的生长。
原文来源：Boelens, M. C., et al. (2014). "Exosome Transfer from Stromal to Breast Cancer Cells Regulates Therapy Resistance Pathways." Cell 159(3): 499-513.
Highlights
- Exosome transfer from stromal to breast cancer cells instigates antiviral signaling
- RNA in exosomes activates antiviral STAT1 pathway through RIG-I
- STAT1 cooperates with NOTCH3 to expand therapy-resistant cells
- Antiviral/NOTCH3 pathways predict NOTCH activity and resistance in primary tumors
Summary
Stromal communication with cancer cells can influence treatment response. We show that stromal and breast cancer (BrCa) cells utilize paracrine and juxtacrine signaling to drive chemotherapy and radiation resistance. Upon heterotypic interaction, exosomes are transferred from stromal to BrCa cells. RNA within exosomes, which are largely noncoding transcripts and transposable elements, stimulates the pattern recognition receptor RIG-I to activate STAT1-dependent antiviral signaling. In parallel, stromal cells also activate NOTCH3 on BrCa cells. The paracrine antiviral and juxtacrine NOTCH3 pathways converge as STAT1 facilitates transcriptional responses to NOTCH3 and expands therapy-resistant tumor-initiating cells. Primary human and/or mouse BrCa analysis support the role of antiviral/NOTCH3 pathways in NOTCH signaling and stroma-mediated resistance, which is abrogated by combination therapy with gamma secretase inhibitors. Thus, stromal cells orchestrate an intricate crosstalk with BrCa cells by utilizing exosomes to instigate antiviral signaling. This expands BrCa subpopulations adept at resisting therapy and reinitiating tumor growth.
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