血小板衍生生长因子-AA介导间充质基质细胞向头颈部鳞状细胞癌肿瘤微环境的趋化作用。

PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment.

作者信息

Watts Tammara L, Cui Ruwen, Szaniszlo Peter, Resto Vicente A, Powell Don W, Pinchuk Irina V

机构信息

Department of Otolaryngology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77555-0521, USA.

Internal Medicine, Division of Gastroenterology, University of Texas Medical Branch, Galveston, TX, 77555, USA.

出版信息

J Transl Med. 2016 Dec 8;14(1):337. doi: 10.1186/s12967-016-1091-6.

DOI:10.1186/s12967-016-1091-6

PMID:27931212

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5146849/

Abstract

BACKGROUND

The robust desmoplasia associated with head and neck squamous cell carcinoma (HNSCC) suggests that the tumor microenvironment may be an important component in the pathophysiology of this cancer. Moreover, the high recurrence rate and poor clinical response to chemotherapy and radiation treatment further underscores that the non-cancerous cells of the microenvironment, such as mesenchymal stromal cells (MSCs), cancer associated fibroblasts (CAFs), and pericytes, may be important in the pathophysiology of HNSCC.

METHODS

Confocal microscopy and immunohistomchemistry approaches were used to identify MSCs tumor microenvironment from patients with oral cavity and oral pharyngeal squamous cell carcinoma (SCC). In vitro Boyden chamber assays and multiplex magnetic bead assays were used to measure MSC chemotaxis and to identify the chemokines secreted by JHU-011, -012, -019, three cells lines derived from patients with oral pharyngeal SCC.

RESULTS

We show here that MSCs reside in the tumor microenvironment of patients with oral cavity and oral pharyngeal SCC and are recruited via paracrine mediated tumor cell secretion of (platelet derived growth factor) PDGF-AA. The MSC markers CD90, CD105, and gremlin-1 were found to co-localize on cells within the tumor microenvironment in oral cavity SCC specimens distinct from α-smooth muscle actin staining CAFs. The conditioned media from JHU-011, -012, and -019 caused a significant increase in MSC migration (>60%) and invasion (>50%; p < 0.0001) compared to oral keratinocyte (OKT) controls. Tumor cell induced MSC chemotaxis appears to be mediated through paracrine secretion of PDGF-AA as inhibition of the PDGF-AA receptor, PDGFR-α but not PDGFR-β, resulted in near arrest of MSC chemotaxis (p < 0.0001).

CONCLUSIONS

Tumor microenvironment expression of PDGFR-α has been shown to correlate with a worse prognosis in patients with prostate, breast, ovarian, non-small cell lung cancer and osteosarcoma. This is the first evidence that a similar signaling paradigm may be present in HNSCC. PDGFR-α inhibitors have not been studied as adjunctive treatment options in the management of HNSCC and may prove to be an important driver of the malignant phenotype in this setting.

摘要

背景

头颈部鳞状细胞癌（HNSCC）相关的显著促结缔组织增生表明肿瘤微环境可能是这种癌症病理生理学的一个重要组成部分。此外，高复发率以及对化疗和放疗的临床反应不佳进一步强调，微环境中的非癌细胞，如间充质基质细胞（MSCs）、癌症相关成纤维细胞（CAFs）和周细胞，可能在HNSCC的病理生理学中起重要作用。

方法

采用共聚焦显微镜和免疫组织化学方法，从口腔和口咽鳞状细胞癌（SCC）患者中鉴定MSCs肿瘤微环境。体外Boyden小室试验和多重磁珠试验用于测量MSCs趋化性，并鉴定从口咽SCC患者衍生的三种细胞系JHU - 011、- 012、- 019分泌的趋化因子。

结果

我们在此表明，MSCs存在于口腔和口咽SCC患者的肿瘤微环境中，并通过旁分泌介导的肿瘤细胞分泌（血小板衍生生长因子）PDGF - AA被募集。发现MSCs标志物CD90、CD105和gremlin - 1在口腔SCC标本的肿瘤微环境中的细胞上共定位，这与α - 平滑肌肌动蛋白染色的CAFs不同。与口腔角质形成细胞（OKT）对照相比，JHU - 011、- 012和- 019的条件培养基导致MSCs迁移显著增加（>60%）和侵袭显著增加（>50%；p < 0.0001）。肿瘤细胞诱导的MSCs趋化似乎是通过PDGF - AA的旁分泌分泌介导的，因为抑制PDGF - AA受体PDGFR - α而非PDGFR - β导致MSCs趋化几乎停滞（p < 0.0001）。