Periostin Exon-21 Antibody Neutralization of Triple-Negative Breast Cancer Cell-Derived Periostin Regulates Tumor-Associated Macrophage Polarization and Angiogenesis.
Periostin Exon-21 Antibody Neutralization of Triple-Negative Breast Cancer Cell-Derived Periostin Regulates Tumor-Associated Macrophage Polarization and Angiogenesis.
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骨膜蛋白外显子21抗体中和三阴性乳腺癌细胞衍生的骨膜蛋白调节肿瘤相关的巨噬细胞极化和血管生成。
DOI：
10.3390/cancers13205072
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发表时间：
2021-10-11
期刊：
影响因子：
5.2
通讯作者：
Morishita R
中科院分区：
文献类型：
--
作者：
Fujikawa T;Sanada F;Taniyama Y;Shibata K;Katsuragi N;Koibuchi N;Akazawa K;Kanemoto Y;Kuroyanagi H;Shimazu K;Rakugi H;Morishita R
尽管乳腺癌的治疗取得了显著进展，但由于缺乏治疗靶分子，除了标准的细胞毒化疗外，对三阴性乳腺癌(TNBC)患者几乎没有其他治疗方法。TNBC仍然是最具侵袭性的亚型，在初次治疗后2年内复发和转移的风险很高。因此，为转移性和复发性TNBC患者开发新的治疗方法是一个尚未得到满足的医学需求。在这项研究中，我们测试了一种新的抗体，针对细胞外Periostin蛋白选择性剪接变体，这些变体是由常规化疗或在内皮间质转化过程中诱导的。这种抗体减少了小鼠异种移植模型中Periostin分泌的TNBC，并伴随着M2肿瘤相关巨噬细胞和肿瘤血管数量的减少。Periostin选择性剪接变异体可能是TNBC患者的一个特异和安全的治疗靶点。Periostin(PN)参与癌症进展的多个过程。在此之前，我们曾报道三阴性乳腺癌(TNBC)中PN的表达与间叶性肿瘤标志物和不良预后相关。在TNBC异种移植模型中，化疗增加了外显子21的PN选择性剪接变异体(ASV)的表达，而外显子21的PN中和抗体(PN-21Ab)的应用克服了化疗耐药，减少了间充质癌细胞的比例。在本研究中，带有外显子21的PN ASV在TNBC进展中的作用已被阐明。我们首先建立了一个稳定的细胞系，携带一个基于荧光的剪接报告。PN阳性的肿瘤相关巨噬细胞()募集和细胞外基质-受体相互作用相关基因的表达高于PN阴性的肿瘤细胞。在异种移植模型中，只有PN阳性细胞启动了肿瘤的形成，而PN-21抗体抑制了肿瘤细胞的生长，并伴随着M2-极化和肿瘤血管数量的减少。这些数据表明，癌细胞衍生的PN ASV可以产生TAMs并调节血管生成，进而建立支持TNBC的微环境。
Despite remarkable advances in breast cancer treatment, few strategies other than standard cytotoxic chemotherapy are available for patients with triple-negative breast cancer (TNBC) due to the lack of therapeutic target molecules. TNBC is still the most aggressive subtype, with a high risk of recurrence and metastasis within 2 years after initial treatment. Thus, there is an unmet medical need to develop new treatments for metastatic and recurrent TNBC patients. In this study we tested a new antibody, targeting extracellular periostin protein alternative splicing variants, which are induced by conventional chemotherapy or during the process of endothelial mesenchymal transition. This antibody reduced periostin-secreting TNBC in a mouse xenograft model, accompanied by a decrease in the number of M2 tumor-associated macrophages and tumor vessels. Periostin alternative splicing variants might be a specific and safe therapeutic target in patients with TNBC. Periostin (Pn) is involved in multiple processes of cancer progression. Previously, we reported that Pn expression is correlated with mesenchymal tumor markers and poor prognosis in triple-negative breast cancer (TNBC). In the TNBC xenograft model, chemotherapy increased expression of a Pn alternative splicing variant (ASV) with exon 21, and administration of the neutralizing antibody against Pn with exon 21 (Pn-21 Ab) overcame chemoresistance with a reduction in the mesenchymal cancer cell fraction. In the present study, the role of Pn ASV with exon 21 in TNBC progression has been addressed. We first established a stable cell line carrying a fluorescence-based splicing reporter. Pn-positive TNBC has higher expression of genes related to tumor-associated macrophage (TAM) recruitment and ECM-receptor interaction than Pn-negative cells. In a xenograft model, only Pn-positive cells initiated tumor formation, and the Pn-21 Ab suppressed tumor cell growth, accompanied by decreased M2 TAM polarization and the number of tumor vessels. These data suggest that cancer cell-derived Pn ASV educates TAMs and regulates angiogenesis, which in turn establishes a microenvironmental niche that is supportive of TNBC.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
对医疗统计信息的自由使用的易于使用的软件“ EZR”的调查。
影响因子：
4.8
作者：
Kanda Y
通讯作者：
Kanda Y
影响因子：
3
作者：
Sun J;Nishiyama T;Shimizu K;Kadota K
通讯作者：
Kadota K
影响因子：
5.2
作者：
Lindsten T;Hedbrant A;Ramberg A;Wijkander J;Solterbeck A;Eriksson M;Delbro D;Erlandsson A
通讯作者：
Erlandsson A
DOI：
10.1074/mcp.m111.014647
发表时间：
2012-04
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Naba A;Clauser KR;Hoersch S;Liu H;Carr SA;Hynes RO
通讯作者：
Hynes RO