Würth Roberto, Bajetto Adriana, Harrison Jeffrey K, Barbieri Federica, Florio Tullio
Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova Genova, Italy ; Centro di Eccellenza per la Ricerca Biomedica, University of Genova Genova, Italy.
Department of Pharmacology and Therapeutics, College of Medicine, University of Florida Gainesville, FL, USA.
Front Cell Neurosci. 2014 May 28;8:144. doi: 10.3389/fncel.2014.00144. eCollection 2014.
Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells. Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascribed to high growth rate, invasiveness to normal brain, marked angiogenesis, ability to escape the immune system and resistance to standard of care therapies. Tumor molecular and cellular heterogeneity severely hinders GBM therapeutic improvement. In particular, a subpopulation of chemo- and radio-therapy resistant tumorigenic cancer stem-like cells (CSCs) is believed to be the main responsible for tumor cell dissemination to the brain. GBM cells display heterogeneous expression levels of CXCR4 and CXCR7 that are overexpressed in CSCs, representing a molecular correlate for the invasive potential of GBM. The microenvironment contribution in GBM development is increasingly emphasized. An interplay exists between CSCs, differentiated GBM cells, and the microenvironment, mainly through secreted chemokines (e.g., CXCL12) causing recruitment of fibroblasts, endothelial, mesenchymal and inflammatory cells to the tumor, via specific receptors such as CXCR4. This review covers recent developments on the role of CXCL12/CXCR4-CXCR7 networks in GBM progression and the potential translational impact of their targeting. The biological and molecular understanding of the heterogeneous GBM cell behavior, phenotype and signaling is still limited. Progress in the identification of chemokine-dependent mechanisms that affect GBM cell survival, trafficking and chemo-attractive functions, opens new perspectives for development of more specific therapeutic approaches that include chemokine-based drugs.
趋化因子在肿瘤发展过程中是关键的自分泌和旁分泌因子。特别是CXCL12，通过其受体CXCR4和CXCR7，通过控制癌细胞的存活、增殖和迁移，以及间接通过血管生成或募集免疫细胞来影响肿瘤进展。胶质母细胞瘤（GBM）是成人中最常见的原发性恶性脑肿瘤，尽管目前采用多模式治疗，但它仍然几乎无法治愈。GBM的侵袭性和复发表型归因于其高生长速率、对正常脑组织的侵袭性、显著的血管生成、逃避免疫系统的能力以及对标准治疗方法的耐药性。肿瘤的分子和细胞异质性严重阻碍了GBM治疗的改善。特别是，一群对化疗和放疗耐药的致瘤性癌症干细胞样细胞（CSCs）被认为是肿瘤细胞向脑内播散的主要原因。GBM细胞显示出CXCR4和CXCR7的异质表达水平，这些受体在CSCs中过度表达，这代表了GBM侵袭潜力的分子关联。微环境在GBM发展中的作用越来越受到重视。CSCs、分化的GBM细胞和微环境之间存在相互作用，主要是通过分泌的趋化因子（如CXCL12），通过特定受体如CXCR4，导致成纤维细胞、内皮细胞、间充质细胞和炎性细胞被募集到肿瘤中。本综述涵盖了CXCL12/CXCR4 - CXCR7网络在GBM进展中的作用的最新进展及其靶向治疗的潜在转化影响。对异质性GBM细胞行为、表型和信号传导的生物学和分子理解仍然有限。在确定影响GBM细胞存活、运输和化学吸引功能的趋化因子依赖性机制方面取得的进展，为开发包括基于趋化因子的药物在内的更特异性治疗方法开辟了新的前景。
