Changes in the vasculature of human brain tumors: Implications for treatment.
Changes in the vasculature of human brain tumors: Implications for treatment.
复制标题
人脑肿瘤脉管系统的变化：对治疗的影响。
DOI：
10.1093/neuonc/noab220
复制
发表时间：
2021
期刊：
影响因子：
15.9
通讯作者：
Elmquist,WilliamF
中科院分区：
文献类型：
--
作者：
Zhang,Wenjuan;Talele,Surabhi;Sarkaria,JannN;Elmquist,WilliamF
Treatment outcomes for malignant brain tumors are poor despite extensive genome-wide molecular characterizations and decades of basic, translational, and clinical research. The complex microenvironment of brain tumors contributes to the dire prognosis for primary and secondary brain malignancies. Tumor vasculature, an essential component of tumor stroma, limits brain tumor distribution, and therefore the efficacy, of otherwise potentially efficacious drugs. 1 The study by Schaffenrath et al 2 offers researchers a perspective of how “better understanding of vasculature changes in human brain malignancies could lead to improved therapeutic targeting of brain tumors.” The authors employ powerful transcriptomic techniques to determine disease-related changes in the vasculature of brain tumors. Schaffenrath et al revealed deregulation of various genes that define blood-brain barrier (BBB) function in glioblastoma (GBM) and brain metastases (BM) of non–small-cell lung cancer. 2 In the normal brain, components of the BBB provide both physical and biochemical barriers to preserve homeostasis. 1 Even though the role of BBB integrity for effective drug exposure and brain tumor therapy is still a matter of debate, limited and heterogeneous drug delivery into GBM and BM is a likely contributor to treatment failure. 1, 3 A heterogeneously disrupted BBB, whether in GBM or BM, can limit the distribution of therapies to the entirety of the tumor, which may significantly impair the efficacy of otherwise potentially curative therapies. Importantly, disruption of the BBB also may be heterogeneous with regards to physicochemical properties of drugs such that accumulation and detection of gadolinium-based contrast agents on MRI may not correspond with distribution of small or large molecule therapeutics. This delivery-efficacy hurdle points to the need for a clear understanding of the impact of tumor-induced changes in the BBB and surrounding stroma on drug delivery. One mechanism of the BBB that restricts access of therapeutic agents to the tumor is the ATP-binding cassette (ABC) transporters expressed on endothelial cells (EC) at BBB and in tumor cells themselves. Schaffenrath et al reported profound alterations in the expression of ABC transporters in GBM and BM vasculature by performing RNA sequencing of EC isolated from primary and secondary brain tumors. 2 The ABCC3 gene, encoding multidrug resistance-associated protein 3 (MRP3), is upregulated in both GBM and BM vasculature. The overexpression of MRP3 may limit the brain distribution of cisplatin, which is commonly used for lung cancer and may contribute to resistance of BM to systemic chemotherapy. 4 Importantly, reduced protein level of P-glycoprotein (P-gp, encoded by ABCB1), one of the predominant efflux transporters, is observed in GBM vasculature. 2 These findings suggest that changes in expression of active efflux transporters in the vasculature of brain tumor, as well as in the GBM cells, 5 may influence drug delivery and hence efficacy (Figure 1). In addition to the efflux transporters, various solute carriers (SLC transporters) at the BBB also have essential roles in the maintenance of brain homeostasis. The upregulated expression of genes encoding amino acid, nucleobase and nucleoside transporters indicates altered metabolic requirements of GBM EC, which implies that modified anticancer drugs such as amino acid-based prodrugs might enhance drug delivery to GBM. Schaffenrath et al found deregulation in the expression of a variety of SLC transporters in brain tumor vasculature. Protoncoupled amino acid transporter 1 (PAT1, encoded by SLC36A1) is variably …
