Heterogeneity and chimerism of endothelial cells revealed by single-cell transcriptome in orthotopic liver tumors

Abstract

The liver is a common host organ for cancer, either through lesions that arise in liver epithelial cells [e.g., hepatocellular carcinoma (HCC)] or as a site of metastasis by tumors arising in other organs (e.g., colorectal cancer). However, the changes that occur in liver stromal cells in response to cancer have not been fully characterized, nor has it been determined whether the different sources of liver cancer induce distinct stromal changes. Here, we performed single-cell profiling of liver stromal cells from mouse models of induced spontaneous liver cancer or implanted colorectal liver metastases, with a focus on tumor endothelial cells (ECs). While ECs in liver tissue adjacent to cancerous lesions (so-called adjacent normal) corresponded to liver zonation phenotypes, their transcriptomes were also clearly altered by the presence of a tumor. In comparison, tumor EC transcriptomes show stronger similarities to venous than sinusoidal ECs. Further, tumor ECs, independent of tumor origin, formed distinct clusters displaying conserved “tip-like” or “stalk-like” characteristics, similar to ECs from subcutaneous tumors. However, they also carried liver-specific signatures found in normal liver ECs, suggesting an influence of the host organ on tumor ECs. Our results document gene expression signatures in ECs in liver cancer and show that the host organ, and not the site of tumor origin (liver versus colorectal), is a primary determinant of EC phenotype. In addition, primarily in tumors, we further defined a cluster of chimeric cells that expressed both myeloid and endothelial cell markers and might play a role in tumor angiogenesis.

RETRACTED: Mitofusin-2 Enhances Mitochondrial Contact With the Endoplasmic Reticulum and Promotes Diabetic Cardiomyopathy

“…The Lipofectamine 2000 mixture was then combined with the siRNA against Mfn2 and incubated for 30 min at room temperature. Subsequently, the cell serum in the six-well plate was removed and the cells were gently rinsed with phosphate-buffered saline ( Zhang L. et al, 2020 ; Zhao et al, 2020 ). Then, 1.6 ml of the serum-free medium was added, followed by the siRNA/Lipofectamine mixture, and the cells were returned to the incubator.…”

RETRACTED: Novel Insights Into the Role of Mitochondria-Derived Peptides in Myocardial Infarction

“…Coronary artery atherosclerosis, characterized by lipid deposition, foam cell formation, and accumulation of cholesterol in the arterial wall, is the leading cause of myocardial ischemia and coronary artery disease (Tabas et al, 2007;Lyu et al, 2015;Sawashita et al, 2020;Zhao et al, 2020). Excessive production of ROS, caused by long-term occlusion of the coronary artery, enhances oxidative stress and inflammation, resulting in vascular endothelial dysfunction and accelerated formation of atherosclerotic plaques (Lu et al, 2020;Watanabe et al, 2020;Wincewicz and Woltanowski, 2020;Yang Q. K. et al, 2020).…”

[Retracted] Protective Effect of Nicorandil on Cardiac Microvascular Injury: Role of Mitochondrial Integrity

“…The endothelial barrier function is highly dependent on the expression of VE-cadherin that participates in endothelial filtration and resistance to substances in the blood through local gap junctions [ 53 , 54 ]. IRI is characterized by reduced VE-cadherin expression, causing leakage of inflammatory cells into the subendothelial myocardium [ 55 – 57 ]. Although reperfusion-induced moderate inflammatory response helps to remove necrotic tissue and thus promote the reconstruction of the infarcted myocardium, excessive inflammation induces residual myocyte dysfunction, exacerbating the myocardial injury and inducing oxidative stress in the myocardium and endothelial cells [ 37 , 58 , 59 ].…”