Cancer-on-a-Chip: Models for Studying Metastasis

Zhang, Xiaojun; Karim, Mazharul; Hasan, Md. Mahedi; Hooper, Jacob; Wahab, Riajul; Roy, Sourav; Al-Hilal, Taslim A.

doi:10.3390/cancers14030648

Cited by 34 publications

(27 citation statements)

References 74 publications

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“…Albeit these are exciting findings, one of the major limitations of our study is that all experiments were conducted in vitro, which could not mimic the real in vivo tumor context, especially the immune microenvironment. To resolve this, the recent in vitro organon-a-chip and advanced microphysiological systems [38,39], which could better capitulate the immune microenvironment, may provide more suitable models. Additionally, more different OC cell lines should be studied, and more in vivo data should be collected before all these observations can reach significance in a clinical setting.…”

Section: Discussionmentioning

confidence: 99%

Combined Usage of MDK Inhibitor Augments Interferon-γ Anti-Tumor Activity in the SKOV3 Human Ovarian Cancer Cell Line

Tan²,

Zhao³

et al. 2022

Biomedicines

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Ovarian cancer (OC) is a particularly lethal disease due to intratumoral heterogeneity, resistance to traditional chemotherapy, and poor response to targeted therapy and immunotherapy. Interferon-γ (IFN-γ) is an attractive therapeutic cytokine, with positive responses achieved in multiple OC clinical trials. However, clinical application of IFN-γ in OC is still hindered, due to the severe toxicity when used at higher levels, as well as the considerable pro-metastatic adverse effect when used at lower levels. Thus, an effective combined intervention is needed to enhance the anti-tumor efficacy of IFN-γ and to suppress the IFN-γ-induced metastasis. Here, we uncovered that OC cells develop an adaptive strategy by upregulating midkine (MDK) to counteract the IFN-γ-induced anti-tumor activity and to fuel IFN-γ-induced metastasis. We showed that MDK is a critical downstream target of IFN-γ in OC, and that this regulation acts in a dose-dependent manner and is mediated by STAT1. Gain-of-function studies showed that MDK overexpression promotes cell proliferation and metastasis in OC, indicating that IFN-γ-activated MDK may antagonize IFN-γ in inhibiting OC proliferation but synergize IFN-γ in promoting OC metastasis. Subsequently, we assessed the influence of MDK inhibition on IFN-γ-induced anti-proliferation and pro-metastasis effects using an MDK inhibitor (iMDK), and we found that MDK inhibition robustly enhanced IFN-γ-induced growth inhibition (all CIs < 0.1) and reversed IFN-γ-driven epithelial-to-mesenchymal transition (EMT) and metastasis in OC in vitro. Collectively, these data identify an IFN-γ responsive protein, MDK, in counteracting anti-proliferation while endowing the pro-metastatic role of IFN-γ in cancer treatment, and we therefore propose the combined utilization of the MDK inhibitor in IFN-γ-based therapies in future OC treatment.

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Section: Discussionmentioning

confidence: 99%

Combined Usage of MDK Inhibitor Augments Interferon-γ Anti-Tumor Activity in the SKOV3 Human Ovarian Cancer Cell Line

Tan²,

Zhao³

et al. 2022

Biomedicines

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“…The endothelial barrier of blood and lymphatic vessels can be penetrated by these cells and travel as circulating tumor cells (CTCs) in the body. CTCs that survive in the circulation can penetrate through the vascular endothelium back to a second organ—usually the liver, lung, brain, or bone ( Figure 4 (Da)) [ 175 , 176 , 177 , 178 ]. After infiltrating new organs, CTCs undergo an EMT that promotes the survival of CTCs in the tissue parenchyma [ 177 , 179 ].…”

Section: Ooc For Tumor Modelingmentioning

confidence: 99%

Recent Advances of Organ-on-a-Chip in Cancer Modeling Research

Liu

Zhang

et al. 2022

Biosensors

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Although many studies have focused on oncology and therapeutics in cancer, cancer remains one of the leading causes of death worldwide. Due to the unclear molecular mechanism and complex in vivo microenvironment of tumors, it is challenging to reveal the nature of cancer and develop effective therapeutics. Therefore, the development of new methods to explore the role of heterogeneous TME in individual patients’ cancer drug response is urgently needed and critical for the effective therapeutic management of cancer. The organ-on-chip (OoC) platform, which integrates the technology of 3D cell culture, tissue engineering, and microfluidics, is emerging as a new method to simulate the critical structures of the in vivo tumor microenvironment and functional characteristics. It overcomes the failure of traditional 2D/3D cell culture models and preclinical animal models to completely replicate the complex TME of human tumors. As a brand-new technology, OoC is of great significance for the realization of personalized treatment and the development of new drugs. This review discusses the recent advances of OoC in cancer biology studies. It focuses on the design principles of OoC devices and associated applications in cancer modeling. The challenges for the future development of this field are also summarized in this review. This review displays the broad applications of OoC technique and has reference value for oncology development.

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“…Because of its high versatility and robust reproducibility, microfluidic vascular models have been used for pre-clinical assays, such as studies of anti-metastatic drug responses and immunotherapy. Previous reviews have summarized tumor extravasation studies using microfluidic vascular models (57,(71)(72)(73)(74)(75), thus we only highlight here the recently published works.…”

Section: Microfluidic Vascular Models To Study Tumor Cell Extravasationmentioning

confidence: 99%

Microfluidic vascular models of tumor cell extravasation

et al. 2022

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Emerging microfluidic disease models have amply demonstrated their value in many fields of cancer research. These in vitro technologies recapitulate key aspects of metastatic cancer, including the process of tumor cell arrest and extravasation at the site of the metastatic tumor. To date, extensive efforts have been made to capture key features of the microvasculature to reconstitute the pre-metastatic niche and investigate dynamic extravasation behaviors using microfluidic systems. In this mini-review, we highlight recent microfluidic vascular models of tumor cell extravasation and explore how this approach contributes to development of in vitro disease models to enhance understanding of metastasis in vivo.

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Cancer-on-a-Chip: Models for Studying Metastasis

Cited by 34 publications

References 74 publications

Combined Usage of MDK Inhibitor Augments Interferon-γ Anti-Tumor Activity in the SKOV3 Human Ovarian Cancer Cell Line

Combined Usage of MDK Inhibitor Augments Interferon-γ Anti-Tumor Activity in the SKOV3 Human Ovarian Cancer Cell Line

Recent Advances of Organ-on-a-Chip in Cancer Modeling Research

Microfluidic vascular models of tumor cell extravasation

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