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Theranostics 2021; 11(4):1991-2005. doi:10.7150/thno.50613 This issue Cite

Research Paper

Remodeling cancer stemness by collagen/fibronectin via the AKT and CDC42 signaling pathway crosstalk in glioma

Chuanhong Zhong^1,2,3,4, Bei Tao⁵, Fangli Tang⁶, Xiaobo Yang^1,2,3,4, Tangming Peng^1,2,3,4, Jian You^1,2,3,4, Kaiguo Xia^1,2,3,4, Xiangguo Xia^1,2,3,4, Ligang Chen^1,2,3,4✉, Lilei Peng^1,2,3,4✉

1. Department of Neurosurgery, Affiliated Hospital of Southwest Medical University, Luzhou China.
2. Sichuan Clinical Research Center for Neurosurgery, Luzhou, China.
3. Academician (Expert) Workstation of Sichuan Province, Luzhou China.
4. Neurological Disease and Brain Function Laboratory, Luzhou, China.
5. Department of Rheumatism, Affiliated Hospital of Southwest Medical University, Luzhou, China.
6. The Second People's Hospital of Yibin, Yibin, China.

✉ Corresponding authors: Ligang Chen, MD, PhD or Lilei Peng, MD, PhD; 1. Department of Neurosurgery, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China, 2. Sichuan Clinical Research Center for Neurosurgery, Luzhou, China, 646000, 3. Academician (expert) Workstation of Sichuan Province, 4. Neurological Disease and Brain Function Laboratory (Luzhou, Sichuan); E-mail: chenligang199066com or neurosurgeryedu.cn. More

Abstract

Cancer development is a complex set of proliferative progression, which arises in most cases via multistep pathways associated with various factors, including the tumor microenvironment and extracellular matrix. However, the underlying mechanisms of cancer development remain unclear and this study aimed to explore the role of extracellular matrix in glioma progression.

Methods: The expression of type I collagen and fibronectin in tumor tissues from glioma patients was examined by immunofluorescence staining. The correlations between collagen/fibronectin and glioma progression were then analyzed. A 3D collagen/fibronectin cultured system was established for tumor cells culture in vitro. Quantitative, real-time PCR and western blot were used to detect PI3K/ATK and CDC42 signals associated proteins expression in glioma. We used in vitro Cell Counting Kit-8, colony formation, and tumorigenesis assays to investigate the function of PI3K/AKT and CDC42 signals associated proteins. A xenograft glioma mice model was also used to study the anticancer effects of integrin inhibitor in vivo.

Results: Our study demonstrated that type I collagen and fibronectin collaborate to regulate glioma cell stemness and tumor growth. In a 3D collagen/fibronectin culture model, glioma cells acquired tumorigenic potential and revealed strengthened proliferative characteristics. More significantly, collagen/fibronectin could facilitate the activation of PI3K/AKT/SOX2 and CDC42/YAP-1/NUPR1/Nestin signaling pathways via integrin αvβ3, eliciting sustained tumor growth and cancer relapse. Combination of the integrin signaling pathway inhibitor and the chemotherapeutic agent efficiently suppressed glioma cell proliferation and tumorigenic ability.

Conclusion: We demonstrated that type I collagen and fibronectin could collaborate to promote glioma progression through PI3K/AKT/SOX2 and CDC42/YAP-1/NUPR1/Nestin signaling pathways. Blockade of the upstream molecular integrin αvβ3 revealed improved outcome in glioma therapy, which provide new insights for eradicating tumors and reducing glioma cancer relapse.

Keywords: collagen, fibronectin, glioma, PI3K/AKT, CDC42

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