CRISPR-Cas9-Mediated Silencing of CD44 in Human Highly Metastatic Osteosarcoma Cells

Liu, Tang; Yan, Zuyun; Liu, Yong; Choy, Edwin; Hornicek, Francis J.; Mankin, Henry J.; Duan, Zhenfeng

doi:10.1159/000489072

Cited by 37 publications

(28 citation statements)

References 36 publications

(61 reference statements)

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“…Unexpectedly, high CD44 expression in primary tumor also appeared to improve survival. The latter data are not significant, but appear to be counter‐intuitive and contradict recent meta‐analyses studies 30 . Thus, larger studies are required to resolve this issue.…”

Section: Resultsmentioning

confidence: 56%

“…Unexpectedly, high CD44 expression in primary tumors appeared to even improve survival (Figure 6B). The latter result is not statistically significant and contradictory to recent meta‐analyses demonstrating that increased CD44 expression in primary tumors predicts poor patient survival 30 . Nevertheless, it should be taken into consideration that CD44 may participate in both growth and metastasis‐promoting or metastasis‐suppressive processes, which depend on cellular contexts and environmental conditions 10,47 .…”

Section: Discussionmentioning

confidence: 73%

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

Klemm

Gerardo-Ramírez

et al. 2020

Intl Journal of Cancer

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Merlin is a versatile tumor suppressor protein encoded by the NF2 gene. Several lines of evidence suggest that Merlin exerts its tumor suppressor activity, at least in part, by forming an inhibitory complex with cluster of differentiation 44 (CD44). Consistently, numerous NF2 mutations in cancer patients are predicted to perturb the interaction of Merlin with CD44. We hypothesized that disruption of the Merlin‐CD44 complex through loss of Merlin, unleashes putative tumor‐ or metastasis‐promoting functions of CD44. To evaluate the relevance of the Merlin‐CD44 interaction in vivo, we compared tumor growth and progression in Cd44‐positive and Cd44‐negative Nf2‐mutant mice. Heterozygous Nf2‐mutant mice were prone to developing highly metastatic osteosarcomas. Importantly, while the absence of the Cd44 gene had no effect on the frequency of primary osteosarcoma development, it strongly diminished osteosarcoma metastasis formation in the Nf2‐mutant mice. In vitro assays identified transendothelial migration as the most prominent cellular phenotype dependent on CD44. Adhesion to endothelial cells was blocked by interfering with integrin α4β1 (very late antigen‐4, VLA‐4) on osteosarcoma cells and CD44 upregulated levels of integrin VLA‐4 β1 subunit. Among other putative functions of CD44, which may contribute to the metastatic behavior, the passage through the endothelial cells also appears to be critical in vivo, as CD44 significantly promoted formation of lung metastasis upon intravenous injection of osteosarcoma cells into immunocompromised mice. Altogether, our results strongly suggest that CD44 plays a metastasis‐promoting role in the absence of Merlin.

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Section: Resultsmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 73%

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

Klemm

Gerardo-Ramírez

et al. 2020

Intl Journal of Cancer

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“…A meta‐analysis was performed to evaluate the clinical relation between TP53 mutations and overall survival of osteosarcoma patients. Briefly, the meta‐analysis was performed as described before . The details of meta‐analysis were described in the Supplementary Materials.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, the meta-analysis was performed as described before. 23 The details of meta-analysis were described in the Supplementary Materials.…”

Section: Meta-analysismentioning

confidence: 99%

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

Tang

Seebacher

et al. 2019

Journal Orthopaedic Research

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Mutant TP53 is a promising therapeutic target in cancers. Considering the current challenges facing the clinical treatment of cancer, as well as the urgent need to identify novel therapeutic targets in osteosarcomas, we aimed to evaluate the clinical significance of mutant TP53 in osteosarcoma patients and to explore the therapeutic effect of targeting mutant TP53 in osteosarcomas. We performed a meta‐analysis to investigate the relationship between mutant TP53 and the overall survival of patients with osteosarcoma. A CRISPR‐Cas9 system and a TP53 inhibitor, NSC59984, were also used to specifically knock‐out and inhibit mutant TP53 in the human osteosarcoma cell lines, KHOS, and KHOSR2. The meta‐analysis demonstrated that mutations in the TP53 gene could be used to predict a poor 2‐year survival in osteosarcoma patients. We also demonstrated that the expression of mutant TP53 in human osteosarcoma cell lines can be efficiently knocked‐out using CRISPR‐Cas9, and this decreased the proliferation, migration, and tumor formation activity of these osteosarcoma cells. Moreover, drug sensitivity to doxorubicin was increased in these TP53 knock‐out osteosarcoma cells. NSC59984 also showed similar anti‐tumor effects as CRISPR‐Cas9 targeted TP53 in the osteosarcoma cells in vitro. We have also demonstrated that the knock‐out or inhibition of mutant TP53 decreased the expression of the oncogene IGF‐1R, anti‐apoptotic proteins Bcl‐2, and Survivin in osteosarcoma cells. Collectively, these results suggest that mutant TP53 is a promising therapeutic target in osteosarcomas. Therefore, further studies exploring novel strategies to target mutant TP53 may help improve the treatment outcomes of osteosarcoma patients in the clinic. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

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“…Of note, the expression of CD44 is significantly higher in metastatic and recurrent OS patient tumor specimens compared to primary tumor tissues [ 54 ]. Therapeutically, the proliferation and spheroid formation of OS cells is inhibited in 3-D culture when CD44 is silenced [ 52 ]. In an orthotopic mouse model of OS, injection with CD44 overexpressing OS cells resulted in increased primary tumor formation and lung metastasis, which was dependent on the HA to CD44 interaction [ 55 ].…”

Section: Ecm Components and Their Function In Osmentioning

confidence: 99%

The role of extracelluar matrix in osteosarcoma progression and metastasis

Cui

Dean

Hornicek

et al. 2020

J Exp Clin Cancer Res

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Osteosarcoma (OS) is the most common primary bone malignancy and responsible for considerable morbidity and mortality due to its high rates of pulmonary metastasis. Although neoadjuvant chemotherapy has improved 5-year survival rates for patients with localized OS from 20% to over 65%, outcomes for those with metastasis remain dismal. In addition, therapeutic regimens have not significantly improved patient outcomes over the past four decades, and metastases remains a primary cause of death and obstacle in curative therapy. These limitations in care have given rise to numerous works focused on mechanisms and novel targets of OS pathogenesis, including tumor niche factors. OS is notable for its hallmark production of rich extracellular matrix (ECM) of osteoid that goes beyond simple physiological growth support. The aberrant signaling and structural components of the ECM are rich promoters of OS development, and very recent works have shown the specific pathogenic phenotypes induced by these macromolecules. Here we summarize the current developments outlining how the ECM contributes to OS progression and metastasis with supporting mechanisms. We also illustrate the potential of tumorigenic ECM elements as prognostic biomarkers and therapeutic targets in the evolving clinical management of OS.

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CRISPR-Cas9-Mediated Silencing of CD44 in Human Highly Metastatic Osteosarcoma Cells

Cited by 37 publications

References 36 publications

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

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

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

The role of extracelluar matrix in osteosarcoma progression and metastasis

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