TRAIL-R2 promotes skeletal metastasis in a breast cancer xenograft mouse model

Abstract

Despite improvements in detection, surgical approaches and systemic therapies, breast cancer remains typically incurable once distant metastases occur. High expression of TRAIL-R2 was found to be associated with poor prognostic parameters in breast cancer patients, suggesting an oncogenic function of this receptor. In the present study, we aimed to determine the impact of TRAIL-R2 on breast cancer metastasis. Using an osteotropic variant of MDA-MB-231 breast cancer cells, we examine the effects of TRAIL-R2 knockdown in vitro and in vivo. Strikingly, in addition to the reduced levels of the proliferation-promoting factor HMGA2 and corresponding inhibition of cell proliferation, knockdown of TRAIL-R2 increased the levels of E-Cadherin and decreased migration. In vivo, these cells were strongly impaired in their ability to form bone metastases after intracardiac injection. Evaluating possible underlying mechanisms revealed a strong downregulation of CXCR4, the receptor for the chemokine SDF-1 important for homing of cancers cells to the bone. In accordance, cell migration towards SDF-1 was significantly impaired by TRAIL-R2 knockdown. Conversely, overexpression of TRAIL-R2 upregulated CXCR4 levels and enhanced SDF-1-directed migration. We therefore postulate that inhibition of TRAIL-R2 expression could represent a promising therapeutic strategy leading to an effective impairment of breast cancer cell capability to form skeletal metastases.

Thapsigargin sensitizes human esophageal cancer to TRAIL-induced apoptosis via AMPK activation

“…RNAi-based approaches have been used as therapeutic methods for the treatment of a variety of tumor types 64 65 . In the present study, we injected CHOP-siRNA directly into the abdominal cavities of nude mice burdened by ESCC cell xenografts and found that, at day 20 after the first injection, the mean tumor volume of the tested group was increased by 38.63% compared with the control.…”

Cell death‐independent activities of the death receptors CD95, TRAILR1, and TRAILR2

“…There is furthermore evidence that TRAILinduced cell migration in KRAS-mutated cells is of the mesenchymal type and thus dependent on mutant KRAS-mediated suppression of ROCK activity which drives otherwise, as discussed above, an amoeboid form of cell migration that can also be induced by death receptors. Proliferation, activation of Akt and Src as well as enhanced bone metastasis along with epithelial mesenchymal transition have furthermore been demonstrated in response to TRAILR2 activation in a xenograft model with a highly osteotropic clone of the MDA-MB-231 breast cancer cell line [157]. Noteworthy, in this model, the ability of TRAILR2 to interact with FADD was found to be dispensable for promotion of metastasis, too, but otherwise the molecular basis of the protumoral activity of TRAILR2 has not been evaluated in this study.…”

Human glandular organoid formation in murine engineering chambers after collagenase digestion and flow cytometry isolation of normal human breast tissue single cells

“…While there are now patient‐derived tumor xenograft models to study BC growth and metastasis using either human (Rowan et al, ; Dahibawkar et al, ; Fritsche et al, ; Sp et al, ) or mouse‐derived cancer cell lines (Singh et al, ; Zou et al, ), there is no mouse model for studying normal breast tissue biology such as that required for examining high MD‐associated BC risk. The complex cellular interactions that underpin MD and BC cannot be easily created in an in vitro setting, thus our pilot study demonstrated the value of our murine biochamber as a model to assess altered cellular function in HMD and LMD human mammary tissues.…”