Proteomic and cytokine profiling of a CTRP8-RXFP1 glioma mouse model.

in Biochemical pharmacology by Thatchawan Thanasupawat, Yared Pages Mejia, Santhosh S Anandhan, Yaxiong Guo, Jasneet Tiwana, Adline Fernando, Aleksandra Glogowska, Talia Shafai, Simone daSilva, Nimrat Kaur, Farhana Begum, Rene Zahedi, Sabine Hombach-Klonisch, Thomas Klonisch

TLDR

  • The study findings suggest that the CTRP8-RXFP1 signaling pathway plays a key role in promoting glioblastoma aggressiveness and could be a potential therapeutic target for treatment.

Abstract

Glioblastoma (GB) is the most prevalent and aggressive primary brain tumor with fatal outcome due to a lack of effective treatments. We previously identified C1q-tumor necrosis factor-related protein 8 (CTRP8), a new member of the adiponectin family, as a novel agonist of the relaxin family peptide receptor 1 (RXFP1) and showed that the CTRP8-RXFP1 ligand-receptor system facilitates increased invasiveness and chemoresistance in GB cells. In the present study, we have investigated the role of the CTRP8-RXFP1 signaling axis in glioma progression using an orthotopic mouse model xenografted with human U251 glioma cells stably expressing CTRP8 and RXFP1. Our results demonstrate that this in-vivo U251-CTRP8/RXFP1 glioma model promoted the formation of aggressive, highly proliferative glioma that resulted in significantly shorter survival times of xenografted mice. CTRP8/RXFP1 xenografts showed strongly elevated mitotic activity, increased expression of cathepsin B at the migrating front and promoted a pro-inflammatory tumor microenvironment characterized by a strong upregulation of cytokines, among them eotaxin-2 and-3, interleukin (IL)-6, IL-18 and others. Proteomic analysis of xenografted mouse brain identified both human and mouse proteome signatures unique to CTRP8/RXFP1 xenografts compared to U251 xenografts. In conclusion, our results suggest that co-expression of CTRP8 and RXFP1 promotes signaling pathways that generate unique tissue proteomic and inflammatory cytokine signatures which promote glioma aggressiveness. The CTRP-RXFP1 signaling pathway may represent an effective therapeutic target for the treatment of fast-progressing and currently untreatable GB.

Overview

  • The study investigates the role of C1q-tumor necrosis factor-related protein 8 (CTRP8) and relaxin family peptide receptor 1 (RXFP1) in glioblastoma progression using an orthotopic mouse model.
  • The study used a U251 glioma cell line stably expressing both CTRP8 and RXFP1 to create xenografts in mice.
  • The primary objective of the study was to explore the signaling pathways and molecular signatures associated with CTRP8-RXFP1 co-expression and their potential therapeutic implications.

Comparative Analysis & Findings

  • The study found that CTRP8/RXFP1 xenografts promoted the formation of aggressive, highly proliferative glioma with significantly shorter survival times in xenografted mice.
  • Proteomic analysis identified both human and mouse proteome signatures unique to CTRP8/RXFP1 xenografts compared to U251 xenografts.
  • The CTRP8/RXFP1 xenografts showed strongly elevated mitotic activity, increased expression of cathepsin B at the migrating front, and promoted a pro-inflammatory tumor microenvironment.

Implications and Future Directions

  • The study suggests that the CTRP8-RXFP1 signaling pathway may represent an effective therapeutic target for the treatment of fast-progressing and currently untreatable glioblastoma.
  • Future studies could explore the therapeutic potential of targeting the CTRP8-RXFP1 axis in glioblastoma using targeted therapies or small molecule inhibitors.
  • The study's findings highlight the importance of investigating novel therapeutic strategies for glioblastoma, a disease with a high mortality rate and limited treatment options.
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