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Metastasis-on-a-chip mimicking the progression of kidney cancer in the liver for predicting treatment efficacy.

ABSTRACT: Metastasis is one of the most important factors that lead to poor prognosis in cancer patients, and effective suppression of the growth of primary cancer cells in a metastatic site is paramount in averting cancer progression. However, there is a lack of biomimetic three-dimensional (3D) in vitro models that can closely mimic the continuous growth of metastatic cancer cells in an organ-specific extracellular microenvironment (ECM) for assessing effective therapeutic strategies. Methods: In this metastatic tumor progression model, kidney cancer cells (Caki-1) and hepatocytes (i.e., HepLL cells) were co-cultured at an increasing ratio from 1:9 to 9:1 in a decellularized liver matrix (DLM)/gelatin methacryloyl (GelMA)-based biomimetic liver microtissue in a microfluidic device. Results: Via this model, we successfully demonstrated a linear anti-cancer relationship between the concentration of anti-cancer drug 5-Fluorouracil (5-FU) and the percentage of Caki-1 cells in the co-culture system (R² = 0.89). Furthermore, the Poly(lactide-co-glycolide) (PLGA)-poly(ethylene glycol) (PEG)-based delivery system showed superior efficacy to free 5-FU in killing Caki-1 cells. Conclusions: In this study, we present a novel 3D metastasis-on-a-chip model mimicking the progression of kidney cancer cells metastasized to the liver for predicting treatment efficacy. Taken together, our study proved that the tumor progression model based on metastasis-on-a-chip with organ-specific ECM would provide a valuable tool for rapidly assessing treatment regimens and developing new chemotherapeutic agents.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6929630 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Metastasis-on-a-chip mimicking the progression of kidney cancer in the liver for predicting treatment efficacy.

Wang Yimin Y Wu Di D Wu Guohua G Wu Jianguo J Lu Siming S Lo James J He Yong Y Zhao Chao C Zhao Xin X Zhang Hongbo H Wang ShuQi S

Theranostics 20200101 1

Metastasis is one of the most important factors that lead to poor prognosis in cancer patients, and effective suppression of the growth of primary cancer cells in a metastatic site is paramount in averting cancer progression. However, there is a lack of biomimetic three-dimensional (3D) <i>in vitro</i> models that can closely mimic the continuous growth of metastatic cancer cells in an organ-specific extracellular microenvironment (ECM) for assessing effective therapeutic strategies. <b>Methods: ...[more]

PMID: 31903121

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Project description:BackgroundColorectal cancer (CRC) exhibits a high incidence globally, with the liver being the most common site of distant metastasis. At the time of diagnosis, 20-30% of CRC patients already present with liver metastases. Colorectal liver metastasis (CRLM) is a major cause of mortality among CRC patients. The pathogenesis of CRLM involves complex molecular mechanisms and the hepatic immune microenvironment, but current clinical prevention and treatment are significantly limited. Recent studies have revealed that the major facilitator superfamily domain containing protein-2a (Mfsd2a) plays a pivotal role in the development and metastasis of various cancers. For instance, Mfsd2a inhibits gastric cancer initiation and progression and may impact angiogenesis. However, the mechanisms by which Mfsd2a influences CRC progression and liver metastasis remain unclear.MethodsIn this study, we conducted a survival analysis of Mfsd2a in colorectal cancer using data from the GEPIA and GEO databases, and examined the expression differences between primary tumor (PT) and liver metastasis (LM). We further assessed the clinical significance and prognostic relevance of Mfsd2a through immunohistochemical analysis of tissue samples from 70 CRLM patients. Moreover, Kaplan-Meier analysis was used to perform survival analysis on these patients. The biological function of Mfsd2a in CRLM was confirmed by a series of experiments conducted both in vitro and in vivo. Additionally, we investigated downstream molecular pathways using western blot, Co-immunoprecipitation, immunofluorescence, and mass spectrometry techniques.ResultsWe observed that Mfsd2a expression is reduced in LM compared to PT, and higher Mfsd2a levels are associated with better prognosis in CRLM patients. Furthermore, function assays demonstrated that Mfsd2a suppresses CRC cells proliferation, migration, invasion, and EMT in vitro, while also delaying tumor growth and liver metastasis in vivo. Mechanistically, Mfsd2a interacts with S100A14, enhancing its expression and inhibiting phosphorylation of STAT3. In addition, the STAT3 activator colivelin partially reversed the inhibitory effect of Mfsd2a overexpression on the progression of colorectal cancer and liver metastasis.ConclusionIn summary, Mfsd2a inhibits colorectal cancer progression and liver metastasis by interacting with S100A14, thereby suppressing the phosphorylation of STAT3. Mfsd2a functions as a tumor suppressor in CRLM and could be a promising therapeutic target for treating CRC patients with liver metastasis.

Dataset Information

Metastasis-on-a-chip mimicking the progression of kidney cancer in the liver for predicting treatment efficacy.

Publications

Metastasis-on-a-chip mimicking the progression of kidney cancer in the liver for predicting treatment efficacy.

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