Characterization of a murine model of metastatic human non-small cell lung cancer and effect of CXCR4 inhibition on the growth of metastases

Abstract

Despite successful preclinical testing carried out through the use of subcutaneous xenografted tumors, many anti-cancer agents have gone on to fail in human trials. One potential factor accounting for this discrepancy may relate to the inadequacy of the commonly employed preclinical models to recapitulate the human disease, particularly when it comes to discovery of agents that are effective against advanced disease. Herein, we report the characterization of a NSCLC model and an exploration of the impact that a CXCR4 inhibitor, AMD3100, had on NCI-H1299-derived metastasis. These cells express a variety of metastasis-promoting factors, hence we selected them for a study of their metastatic colonization potential. To accomplish this, luciferase-expressing H1299 (H1299-luc2) cells were inoculated into athymic mice via the intracardiac route. This strategy produced adrenal, bone, ovarian, and pancreatic metastases, sites commonly involved in human metastatic NSCLC. Notably, micro-computed tomography and histological evaluation of the skeletal lesions revealed the presence of extensive osteolysis. To investigate the potential role of CXCR4 in mediating metastatic colonization of tissues, AMD3100 was administered to mice inoculated with H1299-luc2 cells. While this treatment did not appreciably alter the frequency of metastatic colonization, it was able to slow the growth of macrometastases. This model, recapitulating some of the events seen in late-stage human NSCLC, may prove useful in the evaluation of new therapies targeting metastatic disease.

Tubeimoside‑1 inhibits the proliferation and metastasis by promoting miR‑126‑5p expression in non‑small cell lung cancer cells

“…The most obvious feature of NCI-H1299 is its absence of pro-apoptotic p53 expression. Singla et al ( 18 ) and Wu et al ( 19 ) have demonstrated the possibility of metastasis induced by NCI-H1299 cells in mice model. In this study, we showed that TBMS1 blocked the migration and invasion of NCI-H1299 cells significantly, first indicating the anti-metastatic effect of TBMS1 in NSCLC cells.…”

ESE‑1 suppresses the growth, invasion and migration of human NSCLC cells and tumor formation in�vivo

“…We selected the H1299 cell line for further studies due to its potent tumorigenic and metastatic property (21). Using soft agar assay, we identified ESE-1 as a tumor suppressor in human NSCLC cells.…”

Role of Tumor-Derived Chemokines in Osteolytic Bone Metastasis

“…Lung carcinoma metastasis of bone also involves CXCR4/CXCL12 signaling, however, the relative importance of pathway in survival, homing, and osteolysis is not clear ( 105 , 106 ). Recently, CXCR4 was discovered to be a biomarker for NSCLC bone metastasis and presumably expression of this receptor facilitates homing to the CXCL12 expressing bone marrow as observed in other metastatic cancers ( 107 , 108 ).…”

“…As is observed with other cancers, CXCR4 expression correlates with “cancer stem-cell” properties which include a propensity for tumor initiation and metastasis ( 109 , 110 ). However, one study using AMD3100 showed that NSCLC metastatic colonization of bone did not require CXCR4 activity, however, outgrowth of metastases and subsequent osteolysis was dependent on the receptor ( 106 ).…”