CD44 drives aggressiveness and chemoresistance of a metastatic human osteosarcoma xenograft model

Abstract

BackgroundOsteosarcoma is the most common primary malignant bone tumor with a 5 year survival rate of up to 70%. However, patients with metastatic disease have still a very poor prognosis. Osteosarcoma metastasis models are essential to develop novel treatment strategies for advanced disease.MethodsBased on a serial transplantation approach, we have established a U-2 OS osteosarcoma xenograft model with increased metastatic potential and compared it to other metastatic osteosarcoma models from international sources. Subclones with differing invasive potential were compared for genomic gains and losses as well as gene expression changes by several bioinformatic approaches. Based on the acquired results, the effects of a shRNA-mediated CD44 mRNA knockdown on migration, invasion and chemosensitivity were evaluated.ResultsThe CD44 gene was part of an amplified region at chromosome 11p found in both U-2 OS subclones with enhanced metastatic potential but not in parental U-2 OS cells, corresponding with distinct CD44 overexpression. Accordingly, shRNA-mediated CD44 knockdown significantly attenuated osteosarcoma cell migration, invasion, and viability especially in the metastatic subclones of U-2 OS and Saos-2 cells. Metastatic subclones generally were hypersensitive against the integrin inhibitor cilengitide paralleled by alterations in integrin expression pattern following CD44 knock-down. Additionally, attenuation of CD44 expression sensitized these cell models against osteosarcoma chemotherapy with doxorubicin but not methotrexate and cisplatin.ConclusionsThe osteosarcoma xenograft models with increased metastatic potential developed in this study can be useful for identification of mechanisms driving metastasis and resistance towards clinically used and novel therapeutic regimens.

Targeting CD44 by CRISPR-Cas9 in Multi-Drug Resistant Osteosarcoma Cells

“…In meningioma and gastric cancer, high CD44 expression was correlated with tumor cell proliferation and invasion [45,46]. Previous study showed that siRNA-mediated knockdown of CD44 significantly attenuates migration, invasion and viability of osteosarcoma cells [37]. We have similar findings with the application of CD44 sgRNA CRISPR/Cas9.…”

“…Previous studies have noted that knockdown CD44 by shRNA in osteosarcoma cell lines (U2-OS, KHOS) could efficiently decrease the osteosarcoma potential to metastasis [37]. However, the effect of knocking out targeted gene by RNAi-based techniques is neither permanent nor complete [9].…”

Molecular implications of MUC5AC-CD44 axis in colorectal cancer progression and chemoresistance

“…Previously, it was reported that CD44, a transmembrane glycoprotein, is aberrantly expressed in several cancers and regulates cancer cell migration, invasion, and metastasis by interacting with extracellular ligands [35]. It is also considered an important stem cell marker and is responsible for resistance of tumor cells to drugs [20,[36][37][38]. Transmembrane CD44 is a non-tyrosine receptor and transmits its signals through the oncogenic protein Src and activation of down-stream effector molecules.…”

Cluster of differentiation 44 promotes osteosarcoma progression in mice lacking the tumor suppressor Merlin

“…The action of CD44 in murine osteosarcoma appears to parallel osteosarcoma development in humans. CD44 is upregulated in metastatic subclones of human osteosarcoma and promotes lung metastasis formation in an allograft assay 33‐35 …”