IGF1R acts as a cancer-promoting factor in the tumor microenvironment facilitating lung metastasis implantation and progression

被引:60
作者
Alfaro-Arnedo, Elvira [1 ]
Lopez, Iciar P. [1 ]
Pineiro-Hermida, Sergio [2 ]
Canalejo, Marta [1 ]
Gotera, Carolina [3 ,4 ]
Javier Sola, Jesus [5 ]
Roncero, Alejandra [6 ]
Peces-Barba, German [3 ,4 ]
Ruiz-Martinez, Carlos [6 ]
Pichel, Jose G. [1 ,4 ]
机构
[1] Fdn Rioja Salud, Ctr Biomed Res La Rioja CIBIR, Lung Canc & Resp Dis Unit, Logrono, Spain
[2] Spanish Natl Canc Ctr CNIO, Mol Oncol Program, Telomeres & Telomerase Grp, Madrid, Spain
[3] IIS Fdn Jimenez Diaz, Madrid, Spain
[4] CIBERES, Spanish Biomed Res Networking Ctr, Madrid, Spain
[5] Rioja Salud, Pathol Anat Serv, Hosp Univ San Pedro, Logrono, Spain
[6] Rioja Salud, Hosp Univ San Pedro, Pneumol Serv, Logrono, Spain
关键词
FACTOR; 1; RECEPTOR; PROGNOSTIC-FACTOR; DENDRITIC CELLS; GROWTH-FACTORS; UP-REGULATION; T-CELLS; EXPRESSION; ACTIVATION; BLOCKADE; PATHWAY;
D O I
10.1038/s41388-022-02376-w
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Given the long-term ineffectiveness of current therapies and late-stage diagnoses, lung cancer is a leading cause of malignant diseases. Tumor progression is influenced by cancer cell interactions with the tumor microenvironment (TME). Insulin-like growth factor 1 receptor (IGF1R) was reported to affect the TME; however, the role of IGF1R in lung TME has not been investigated. First, we assessed IGF1R genomic alterations and expression in NSCLC patient tissue samples, as well as IGF1R serum levels. Next, we performed tumor heterotopic transplantation and pulmonary metastases in IGF1R-deficient mice using melanoma and Lewis lung carcinoma (LLC) cells. Herein we report increased amplification and mRNA expression, as well as increased protein expression (IGF1R/p-IGF1R) and IGF1R levels in tumor samples and serum from NSCLC patients, respectively. Moreover, IGF1R deficiency in mice reduced tumor growth, proliferation, inflammation and vascularization, and increased apoptosis after tumor heterotopic transplantation. Following induction of lung metastasis, IGF1R-deficient lungs also demonstrated a reduced tumor burden, and decreased expression of tumor progression markers, p-IGF1R and p-ERK1/2. Additionally, IGF1R-deficient lungs showed increased apoptosis and diminished proliferation, vascularization, EMT and fibrosis, along with attenuated inflammation and immunosuppression. Accordingly, IGF1R deficiency decreased expression of p-IGF1R in blood vessels, fibroblasts, tumor-associated macrophages and FOXP3(+) tumor-infiltrating lymphocytes. Our results demonstrate that IGF1R promotes( )metastatic tumor initiation and progression in lung TME. Furthermore, our research indicates that IGF1R could be a potential biomarker for early prediction of drug response and clinical evolution in NSCLC patients.
引用
收藏
页码:3625 / 3639
页数:15
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