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Monitoring imatinib decreasing pericyte coverage and HIF-1α level in a colorectal cancer model by an ultrahigh-field
Xinpeng Hu1, Kunlin Ye1, Shaowei Bo2
1Medical Imaging Center, The First Affiliated Hospital of Jinan University, West Huangpu Avenue No. 613, Guangzhou, 510630, China.
Background:
Excessive pericyte coverage promotes tumor growth, and a downregulation may solve this dilemma. Due to the double-edged sword role of vascular pericytes in tumor microenvironment (TME), indiscriminately decreasing pericyte coverage by imatinib causes poor treatment outcomes. Here, we optimized the use of imatinib in a colorectal cancer (CRC) model in high pericyte-coverage status, and revealed the value of multiparametric magnetic resonance imaging (mpMRI) at 9.4T in monitoring treatment-related changes in pericyte coverage and the TME.
Methods:
CRC xenograft models were evaluated by histological vascular characterizations and mpMRI. Mice with the highest pericyte coverage were treated with imatinib or saline; then, vascular characterizations, tumor apoptosis and HIF-1α level were analyzed histologically, and alterations in the expression of Bcl-2/bax pathway were assessed through qPCR. The effects of imatinib were monitored by dynamic contrast-enhanced (DCE)-, diffusion-weighted imaging (DWI)- and amide proton transfer chemical exchange saturation transfer (APT CEST)-MRI at 9.4T.
Results:
The DCE- parameters provided a good histologic match the tumor vascular characterizations. In the high pericyte coverage status, imatinib exhibited significant tumor growth inhibition, necrosis increase and pericyte coverage downregulation, and these changes were accompanied by increased vessel permeability, decreased microvessel density (MVD), increased tumor apoptosis and altered gene expression of apoptosis-related Bcl-2/bax pathway. Strategically, a 4-day imatinib effectively decreased pericyte coverage and HIF-1α level, and continuous treatment led to a less marked decrease in pericyte coverage and re-elevated HIF-1α level. Correlation analysis confirmed the feasibility of using mpMRI parameters to monitor imatinib treatment, with DCE-derived Ve and Ktrans being most correlated with pericyte coverage, Ve with vessel permeability, AUC with microvessel density (MVD), DWI-derived ADC with tumor apoptosis, and APT CEST-derived MTRasym at 1 µT with HIF-1α.
Conclusions:
These results provided an optimized imatinib regimen to achieve decreasing pericyte coverage and HIF-1α level in the high pericyte-coverage CRC model, and offered an ultrahigh-field multiparametric MRI approach for monitoring pericyte coverage and dynamics response of the TME to treatment.
Insights
Optimizing imatinib treatment in colorectal cancer (CRC) models with high pericyte coverage effectively reduced tumor growth and pericyte levels. Multiparametric MRI (mpMRI) at 9.4T proved valuable for monitoring these treatment-induced changes in the tumor microenvironment (TME).
Area of Science:
- Oncology
- Radiology
- Molecular Biology
Background:
- Excessive pericyte coverage in the tumor microenvironment (TME) fuels tumor growth.
- The dual role of vascular pericytes necessitates optimized therapeutic strategies, as indiscriminate reduction can impair treatment outcomes.
- This study focuses on a colorectal cancer (CRC) model with high pericyte coverage.
Purpose of the Study:
- To optimize imatinib treatment for reducing pericyte coverage in a high-pericyte CRC model.
- To evaluate the utility of ultrahigh-field multiparametric MRI (mpMRI) at 9.4T in monitoring treatment-related changes in pericyte coverage and the TME.
- To establish an effective imatinib regimen and a monitoring approach for high-pericyte CRC.
Main Methods:
- CRC xenograft models with high pericyte coverage were treated with imatinib or saline.
- Histological analyses assessed vascular characteristics, tumor apoptosis, and HIF-1α levels.
- Multiparametric MRI, including dynamic contrast-enhanced (DCE)-, diffusion-weighted imaging (DWI)-, and amide proton transfer chemical exchange saturation transfer (APT CEST)-MRI at 9.4T, monitored treatment effects.
Main Results:
- Optimized imatinib treatment significantly inhibited tumor growth, increased necrosis, and reduced pericyte coverage, vessel permeability, and microvessel density (MVD).
- A 4-day imatinib regimen effectively decreased pericyte coverage and HIF-1α levels, unlike continuous treatment.
- mpMRI parameters, particularly DCE-derived Ve and Ktrans, correlated well with pericyte coverage, vessel permeability, MVD, tumor apoptosis, and HIF-1α levels.
Conclusions:
- An optimized imatinib regimen effectively reduces pericyte coverage and HIF-1α levels in high-pericyte CRC models.
- Ultrahigh-field multiparametric MRI offers a viable approach for monitoring pericyte dynamics and TME responses to treatment.
- This study provides a strategic treatment and monitoring framework for specific CRC subtypes.
