Targeting programmed cell death ligand 1 by CRISPR/Cas9 in osteosarcoma cells

Liao, Yunfei; Chen, Lulu; Feng, Yong; Shen, Jacson K.; Gao, Yan; Coté, Gregory M.; Choy, Edwin; Harmon, David C.; Mankin, Henry J.; Hornicek, Francis J.; Duan, Zhenfeng

doi:10.18632/oncotarget.16326

Cited by 72 publications

(61 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NGS is currently the most important technology for early diagnosis and prognosis, as well as identification of novel predictive biomarkers for available treatments with targeted therapy and immunotherapy for patients with CRC (138). Specifically, the combination of CRISPR/Cas9 technology and immunotherapy would significantly improve patient care by reducing side effects (139,140).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy (Review)

2018

View full text Add to dashboard Cite

Abstract. Colorectal cancer (CRC) results from the progressive accumulation of multiple genetic and epigenetic aberrations within cells. The progression from colorectal adenoma to carcinoma is caused by three major pathways: Microsatellite instability, chromosomal instability and CpG island methylator phenotype. A growing body of scientific evidences suggests that CRC is a heterogeneous disease, and genetic characteristics of the tumors determine their prognostic outcome and response to targeted therapies. Early diagnosis and effective targeted therapies based on a current knowledge of the molecular characteristics of CRC are essential to the successful treatment of CRC. Therefore, the present review summarized the current understanding of the molecular characteristics of CRC, and discussed its implications for diagnosis and targeted therapy.

show abstract

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy (Review)

2018

View full text Add to dashboard Cite

show abstract

“…For instance, knockdown of PD-L1 expression in gastric cancer cells could significantly suppress cell proliferation, migration and invasion ( 89 ). Also, knockout of PD-L1 expression by CRISPR/Cas9 inhibits the spheroid formation of osteosarcoma cells ( 90 ). PD-L1 was shown to promote EMT in esophageal cancer ( 91 ).…”

Section: The Role Of Pd-l1 In Stimulating or Inhibiting Cancermentioning

confidence: 99%

“…PD-L1 induced EMT via activating SREBP-1c in renal cell carcinoma ( 100 ). CRISPR/Cas9 system-mediated PD-L1 disruption increased drug sensitivities for doxorubicin and paclitaxel ( 90 ). The interaction of PD-L1 with PD-1 induced phosphorylation of AKT and ERK, resulting in the activation of PI3K/AKT and MAPK/ERK pathways and increased MDR1 expression in breast cancer cells ( 101 ).…”

Section: The Role Of Pd-l1 In Stimulating or Inhibiting Cancermentioning

confidence: 99%

Tumor-Intrinsic PD-L1 Signaling in Cancer Initiation, Development and Treatment: Beyond Immune Evasion

et al. 2018

View full text Add to dashboard Cite

Although the role of PD-L1 in suppressing the anti-tumor immune response is extensively documented, recent discoveries indicate a distinct tumor-intrinsic role for PD-L1 in modulating epithelial-to-mesenchymal transition (EMT), cancer stem cell (CSC)-like phenotype, metastasis and resistance to therapy. In this review, we will focus on the newly discovered functions of PD-L1 in the regulation of cancer development, describe underlying molecular mechanisms responsible for PD-L1 upregulation and discuss current insights into novel components of PD-L1 signaling. Furthermore, we summarize our current understanding of the link between PD-L1 signaling and the EMT program as well as the CSC state. Tumor cell-intrinsic PD-L1 clearly contributes to cancer stemness, EMT, tumor invasion and chemoresistance in multiple tumor types. Conversely, activation of OCT4 signaling and upregulation of EMT inducer ZEB1 induce PD-L1 expression in cancer cells, thereby suggesting a possible immune evasion mechanism employed by cancer stem cells during metastasis. Our meta-analysis demonstrated that PD-L1 is co-amplified along with MYC, SOX2, N-cadherin and SNAI1 in the TCGA endometrial and ovarian cancer datasets. Further identification of immune-independent PD-L1 functions and characterization of crucial signaling events upstream or downstream of PD-L1 in diverse cancer types and specific cancer subtypes, would provide additional targets and new therapeutic approaches.

show abstract

“…More recent efforts seek to capitalize on the successes seen with immune checkpoint inhibitors in other cancers by extending those regimens to patients with osteosarcoma. Expression of checkpoint molecules like PD-L1 on osteosarcoma cells correlates with metastasis and decreased survival ( 50 , 51 ), and murine studies suggest at least some activity of checkpoint inhibitors in osteosarcoma ( 52 ). Results in human trials using largely single-agent checkpoint inhibitor therapies have, to date, proved disappointing ( 53 , 54 ).…”

Section: Immuno-oncology Of Osteosarcomamentioning

confidence: 99%

Osteosarcoma: Accelerating Progress Makes for a Hopeful Future

2018

View full text Add to dashboard Cite

Patients who develop osteosarcoma in 2017 receive treatment that remains essentially unchanged since the 1970s. Outcomes likewise remain largely unimproved. Large, collaborative, multinational efforts to improve therapy have evaluated strategies leveraging both cytotoxic intensification and immunomodulatory agents. While these have confirmed our capacity to conduct such trials, results have proved largely disappointing. This has motivated efforts to focus on the basic biology of osteosarcoma, where understanding remains poor but has improved significantly. Recent advances have identified characteristic genetic features of osteosarcoma, including profound chromosomal disruption, marked patient-patient heterogeneity, and a paucity of recurrent mutations. Analyses suggest genesis in early catastrophic genetic events, although the nature of the inciting events remains unclear. While p53 and Rb inactivation occurs in most osteosarcomas, the landscape of associated driver mutations has proved extensive. Few mutations recur with high frequency, though patterns continue to emerge that suggest recurrent alterations within specific pathways. Biological pathways implicated in osteosarcoma biology through genetic and other preclinical studies include PI3K/mTOR, WNT/βcatenin, TGFβ, RANKL/NF-κB, and IGF. Unfortunately, clinical studies evaluating targeted agents have to date yielded disappointing results, as have studies examining modern immunotherapeutics. It remains unclear whether this pattern of clinical failures exposes inadequacies of our preclinical models, unrealistic expectations for single-agent responses in heavily pretreated patients, or biology less relevant than suggested. Nearly all patients who succumb to osteosarcoma develop lung metastases, which exhibit marked chemoresistance. Much scientific effort has recently sought to enhance our mechanistic understanding of metastasis biology. This research has potential to reveal novel targets for preventing and treating metastasis and for uncovering key vulnerabilities of osteosarcoma cells. Efforts to implement drug development strategies that leverage clinical studies in veterinary patients have potential to accelerate the translation of novel experimental regimens toward human studies. These could reduce costs and development timelines, prioritize agents, and refine regimens prior to human clinical trials. The rise of philanthropic groups focused on osteosarcoma has enhanced cross-disciplinary and cross-institutional focus and provided much needed resources. Transformative new therapies will likely arise from collaborative, interdisciplinary efforts that extend our understanding of osteosarcoma’s most basic inner workings.

show abstract

Targeting programmed cell death ligand 1 by CRISPR/Cas9 in osteosarcoma cells

Cited by 72 publications

References 34 publications

The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy (Review)

The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy (Review)

Tumor-Intrinsic PD-L1 Signaling in Cancer Initiation, Development and Treatment: Beyond Immune Evasion

Osteosarcoma: Accelerating Progress Makes for a Hopeful Future

Contact Info

Product

Resources

About