Spatiotemporal assessment of spontaneous metastasis formation using multimodal in vivo imaging in HER2+ and triple negative metastatic breast cancer xenograft models in mice

Abstract

BackgroundPreclinical breast cancer models recapitulating the clinical course of metastatic disease are crucial for drug development. Highly metastatic cell lines forming spontaneous metastasis following orthotopic implantation were previously developed and characterized regarding their biological and histological characteristics. This study aimed to non-invasively and longitudinally characterize the spatiotemporal pattern of metastasis formation and progression in the MDA-MB-231-derived triple negative LM2-4 and HER2+ LM2-4H2N cell lines, using bioluminescence imaging (BLI), contrast enhanced computed tomography (CT), fluorescence imaging, and 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography ([18F]FDG-PET).Material and methodsLM2-4, LM2-4H2N, and MDA-MB-231 tumors were established in the right inguinal mammary fat pad (MFP) of female SCID mice and resected 14–16 days later. Metastasis formation was monitored using BLI. Metabolic activity of primary and metastatic lesions in mice bearing LM2-4 or LM2-4H2N was assessed by [18F]FDG-PET. Metastatic burden at study endpoint was assessed by CT and fluorescence imaging following intravenous dual-modality liposome agent administration.ResultsComparable temporal metastasis patterns were observed using BLI for the highly metastatic cell lines LM2-4 and LM2-4H2N, while metastasis formed about 10 days later for MDA-MB-231. 21 days post primary tumor resection, metastases were detected in 86% of LM2-4, 69% of LM2-4H2N, and 60% of MDA-MB-231 inoculated mice, predominantly in the axillary region, contralateral MFP, and liver/lung. LM2-4 and LM2-4H2N tumors displayed high metabolism based on [18F]FDG-PET uptake. Lung metastases were detected as the [18F]FDG-PET uptake increased significantly between pre- and post-metastasis scan. Using a liposomal dual-modality agent, CT and fluorescence confirmed BLI detected lesions and identified additional metastatic nodules in the intraperitoneal cavity and lung.ConclusionsThe combination of complementary anatomical and functional imaging techniques can provide high sensitivity characterization of metastatic disease spread, progression and overall disease burden. The described models and imaging toolset can be implemented as an effective means for quantitative treatment response evaluation in metastatic breast cancer.

Silencing of FTX suppresses pancreatic cancer cell proliferation and invasion by upregulating miR-513b-5p

“…Xenotransplantation model is an ideal animal model for tumor research [51,52]. At present, xenografted mouse models have been established for PC, gastric cancer, breast cancer and other tumors, which maintained the pathological and histological characteristics of the original tumor from multiple perspectives such as histopathology and genetics [53][54][55][56]. In this study, the effects of FTX on PC tumor growth in vivo were investigated by establishing xenotransplantation mouse model.…”

A Novel 4-gene Score to Predict Survival, Distant Metastasis and Response to Neoadjuvant Therapy in Breast Cancer

“…The human metastatic breast cell variant LM2-4 selected in vivo from the parental MDA-MB-231 cell line has been extensively described, with studies based on organ tropic seeding to the lungs and how it can be impacted by surgery and treatment detailed elsewhere [22][23][24][25][26][27][28][29]. However, to date no study has extensively examined the molecular differences that may explain the substantial metastatic phenotype changes between these two cell variants.…”

Integrating Small Animal Irradiators with Functional Imaging for Advanced Preclinical Radiotherapy Research

“…Similarly, BLT has also been successfully integrated into the iSMAART system and shown accurately targeting with quantitative assessment of response in orthotopically implanted, luciferase expressing 4T1 breast cancer cells [64]. BLI is an attractive imaging modality in radiotherapy studies as it can provide target localization information and does not contribute to added dose [65,66], however, research efforts are required to develop robust 3D reconstruction algorithms for true tomographical representation.…”