The tumor-associated fibrotic reactions in microenvironment aggravate glioma chemoresistance

Abstract

Malignant gliomas are one of the most common and lethal brain tumors with poor prognosis. Most patients with glioblastoma (GBM) die within 2 years of diagnosis, even after receiving standard treatments including surgery combined with concomitant radiotherapy and chemotherapy. Temozolomide (TMZ) is the first-line chemotherapeutic agent for gliomas, but the frequent acquisition of chemoresistance generally leads to its treatment failure. Thus, it's urgent to investigate the strategies for overcoming glioma chemoresistance. Currently, many studies have elucidated that cancer chemoresistance is not only associated with the high expression of drug-resistance genes in glioma cells but also can be induced by the alterations of the tumor microenvironment (TME). Numerous studies have explored the use of antifibrosis drugs to sensitize chemotherapy in solid tumors, and surprisingly, these preclinical and clinical attempts have exhibited promising efficacy in treating certain types of cancer. However, it remains unclear how tumor-associated fibrotic alterations in the glioma microenvironment (GME) mediate chemoresistance. Furthermore, the possible mechanisms behind this phenomenon are yet to be determined. In this review, we have summarized the molecular mechanisms by which tumor-associated fibrotic reactions drive glioma transformation from a chemosensitive to a chemoresistant state. Additionally, we have outlined antitumor drugs with antifibrosis functions, suggesting that antifibrosis strategies may be effective in overcoming glioma chemoresistance through TME normalization.

Keywords: antifibrosis therapy; cancer-associate fibroblasts; chemoresistance; glioma; tumor microenvironment (TME); tumor-associated fibrotic reaction.

Figure 1

Glioma-associated fibrosis predicts poor prognosis of glioma patients. (A) The expression analysis of fibrosis-related marker genes COL1A2, COL1A1, COL3A1, COL4A1, COL4A2, COL5A2, COL6A2, COL6A1 in the Proneural (PN), Classical (CL), Mesenchymal (ME), and Neural (NE) GBM subtypes in the CGGA dataset. (B) Kaplan-Meier survival curves indicate that ME and CL GBM subtypes predict a poor prognosis for glioma patients in the CGGA dataset. (C–G) Kaplan-Meier survival curves indicate that the high expression of collagen-related genes (COL1A1, COL3A1, COL4A1, COL5A2, and COL6A1) correlates with a poor prognosis for glioma patients in the GEPIA dataset. (GEPIA dataset includes TCGA LGG and GBM dataset.).

Figure 2

Glioma-associated fibrosis positively correlates with the expression of macrophage marker gene CD163. (A) The expression of fibrosis-related marker genes (COL1A2, COL1A1, COL3A1, COL4A1, COL4A2, COL5A2, COL6A2, COL6A1) and M2 macrophage marker gene (CD163) in low-grade glioma (LGG) and GBM in the GEPIA dataset. (B) Relative CD163 mRNA expression levels of four GBM subtypes in the CGGA dataset. ***p < 0.001. (C) CD163 expression positively correlates with COL1A1 expression in all grade glioma (GEPIA). (D) CD163 expression positively correlates with COL1A1 expression in primary and recurrent glioma (CGGA). (GEPIA dataset includes TCGA LGG and GBM dataset.).

Figure 3

The exploration of antifibrosis-related strategies in glioma treatment (by Figdraw ).

Figure 4

The tumor-associated fibrosis aggravates glioma chemoresistance by reducing the efficacy of drug delivery (by Figdraw ). The TGF-β signaling pathway could be upregulated in glioma after chemotherapy and epithelial-mesenchymal transition (EMT), resulting in the increased collagen synthesis of cancer-associated fibroblasts (CAFs). In the tumor microenvironment (TME), the tumor-associated fibrosis increased the stiffness and rigidity of glioma tissues which in turn impairs the delivery of chemotherapeutic drugs to cancer cells, thus promoting chemoresistance.