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

Abstract

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.

Cell Atlas at Single-Nuclei Resolution of the Adult Human Adrenal Gland and Adrenocortical Adenomas

“…Within the AME, also a high expression of IGF1R , which plays an important role in the adrenocortical tumourigenesis, was observed 41 . Interestingly, an overepression of IGF1R within the tumour microenvironment was reported to promote tumour initiation and progression in lung cancer and medulloblastoma 63,64 .…”

Phospholysine phosphohistidine inorganic pyrophosphate phosphatase suppresses insulin‐like growth factor 1 receptor expression to inhibit cell adhesion and proliferation in gastric cancer

“…Recently, IGF1R has been reported to promote cancer metastasis and drug resistance 39,40 . Patients with high IGF1R expression tend to have shorter overall survival and a higher possibility of metastasis in various types of cancer, such as breast cancer, prostate cancer, and lung cancer 41–43 . Pichel and coworkers 43 found that compared with the normal mouse lung metastasis model, the lung metastasis model of IGF1R‐deficient mice not only inhibited lung tumor proliferation and angiogenesis but also increased cell apoptosis.…”

Telomerase deficiency and dysfunctional telomeres in the lung tumor microenvironment impair tumor progression in NSCLC mouse models and patient-derived xenografts

“…1G . On day (D0), 1 × 10 6 Lewis cells (LL/2 (LLC1) (ATCC® CRL-1642™)) suspended in 100 µl of DMEM or equal volume of DMEM (controls) were injected via the tail vein [ 71 ] of 10–12 weeks old Tert +/+ and G3 Tert −/− male mice (Fig. 1H ).…”