Chondroitin sulfate proteoglycan 4, a targetable oncoantigen that promotes ovarian cancer growth, invasion, cisplatin resistance and spheroid formation.
Chondroitin sulfate proteoglycan 4, a targetable oncoantigen that promotes ovarian cancer growth, invasion, cisplatin resistance and spheroid formation.
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DOI：
10.1016/j.tranon.2021.101318
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发表时间：
2022-03
影响因子：
5
通讯作者：
McCarthy JB
中科院分区：
文献类型：
--
作者：
Yang J;Liao Q;Price M;Moriarity B;Wolf N;Felices M;Miller JS;Geller MA;Bendzick L;Hopps R;Starr TK;O'Connor CH;Tarullo S;Nelson AC;Turley E;Wang J;McCarthy JB
临床-这些研究首次将CSPG 4确定为与卵巢癌患者预后不良相关的癌抗原。肿瘤细胞表达CSPG 4显着增强体内肿瘤扩张和肿瘤侵袭、顺铂耐药性和球体形成。CSPG表达刺激细胞粘附相关途径（例如，粘着斑激酶），其刺激ZEB 1的表达，ZEB 1刺激侵袭和球状体形成。靶向CSPG 4的特定结构域的抗体限制侵袭并促进球状体内的细胞凋亡。这些研究将CSPG 4确定为靶向癌抗原，可以通过限制转移和改善标准治疗化疗反应来改善卵巢癌患者的管理。上皮性卵巢癌（EOC）是一种高度异质性的疾病，包括几种不同的分子亚型和临床实体。尽管手术减积和辅助化疗取得了初步成功，但卵巢上皮性癌患者中化疗耐药肿瘤的复发很常见，并导致总体生存率很低。与卵巢癌相关的广泛遗传和表型异质性阻碍了EOC患者有效预后和预测生物标志物的鉴定。在目前的研究中，我们确定了肿瘤细胞表面癌抗原硫酸软骨素蛋白聚糖4（CSPG 4）作为EOC患者生存率降低的独立危险因素。我们的研究结果表明，CSPG 4促进EOC细胞的侵袭，顺铂耐药和球体形成在体外和肿瘤的扩展在体内。从机制上讲，球状体形成和肿瘤细胞侵袭是由于CSPG 4刺激的间充质转录因子ZEB 1的表达。此外，我们已经开发了一种新的单克隆抗CSGP 4抗体对核心蛋白，限制CSPG 4刺激的ZEB 1表达，肿瘤细胞侵袭，并促进EOC细胞凋亡的核心蛋白的质膜结构域。因此，我们提出CSPG 4表达驱动EOC肿瘤的表型异质性和恶性进展。这些研究进一步证明，CSPG 4表达水平是EOC中的潜在诊断生物标志物，并表明靶向表达这种癌抗原的细胞可以限制EOC患者的复发并改善预后。
Clinical –The studies are the first to identify CSPG4 as an oncoantigen which is associated with poor outcome in patients with ovarian cancer. CSPG4 expression by tumor cells significantly enhances tumor expansion in vivo and tumor invasion, cisplatin resistance and spheroid formation. CSPG expression stimulates cell adhesion related pathways (e.g. Focal Adhesion Kinase) which stimulates expression of ZEB1 which stimulates invasion and spheroid formation. Antibody targeting a specific domain of CSPG4 limits invasion and promotes apoptosis of cells within spheroids. The studies identify CSPG4 as a targetable oncoantigen that could improve ovarian cancer patient management by limiting metastasis and improving standard of care chemotherapy response. Epithelial ovarian cancer (EOC) is a highly heterogeneous disease encompassing several distinct molecular subtypes and clinical entities. Despite the initial success of surgical debulking and adjuvant chemotherapy, recurrence with chemotherapy resistant tumors is common in patients with EOC and leads to poor overall survival. The extensive genetic and phenotypic heterogeneity associated with ovarian cancers has hindered the identification of effective prognostic and predictive biomarkers in EOC patients. In the current studies, we identify a tumor cell surface oncoantigen, chondroitin sulfate proteoglycan 4 (CSPG4), as an independent risk factor for decreased survival of patients with EOC. Our results show that CSPG4 promotes EOC cell invasion, cisplatin resistance and spheroid formation in vitro and tumor expansion in vivo. Mechanistically, spheroid formation and tumor cell invasion are due to CSPG4-stimulated expression of the mesenchymal transcription factor ZEB1. Furthermore, we have developed a novel monoclonal anti-CSGP4 antibody against the juxtamembrane domain of the core protein that limits CSPG4-stimulated ZEB1 expression, tumor cell invasion and promotes EOC apoptosis within spheroid cultures. We therefore propose that CSPG4 expression drives phenotypic heterogeneity and malignant progression in EOC tumors. These studies further demonstrate that CSPG4 expression levels are a potential diagnostic biomarker in EOC and indicate that targeting cells which express this oncoantigen could limit recurrence and improve outcomes in patients with EOC.
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影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
影响因子：
4.7
作者：
Hijaz, M.;Chhina, J.;Rattan, R.
通讯作者：
Rattan, R.
DOI：
10.1083/jcb.201105103
发表时间：
2011-11-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Li XY;Zhou X;Rowe RG;Hu Y;Schlaepfer DD;Ilić D;Dressler G;Park A;Guan JL;Weiss SJ
通讯作者：
Weiss SJ
影响因子：
--
作者：
Deng J;Wang L;Chen H;Hao J;Ni J;Chang L;Duan W;Graham P;Li Y
通讯作者：
Li Y
影响因子：
8.3
作者：
Ampofo E;Schmitt BM;Menger MD;Laschke MW
通讯作者：
Laschke MW