Tumor Cell–Derived Angiopoietin-2 Promotes Metastasis in Melanoma

Abstract

The Angiopoietin (Angpt)-TIE signaling pathway controls vascular maturation and maintains the quiescent phenotype of resting vasculature. The contextual agonistic and antagonistic Tie2 ligand ANGPT2 is believed to be exclusively produced by endothelial cells, disrupting constitutive ANGPT1-TIE2 signaling to destabilize the microvasculature during pathological disorders like inflammation and cancer.However, scattered reports have also portrayed tumor cells as a source of ANGPT2. Employing in situ hybridization-based detection of ANGPT2, we found strong tumor cell expression of ANGPT2 in a subset of melanoma patients. Comparative analysis of biopsies revealed a higher fraction of ANGPT2expressing tumor cells in metastatic versus primary sites. Tumor cell-expressed Angpt2 was dispensable for primary tumor growth, yet in-depth analysis of primary tumors revealed enhanced intratumoral necrosis upon silencing of tumor cell Angpt2 expression in the absence of significant immune and vascular alterations. Global transcriptional profiling of Angpt2-deficient tumor cells identified perturbations in redox homeostasis and an increased response to cellular oxidative stress.Ultrastructural analyses illustrated a significant increase of dysfunctional mitochondria in Angpt2silenced tumor cells, thereby resulting in enhanced ROS production and downstream MAPK stress signaling. Functionally, enhanced ROS in Angpt2-silenced tumor cells reduced colonization potential in vitro and in vivo. Taken together, these findings uncover the hitherto unappreciated role of tumor cellexpressed ANGPT2 as an autocrine positive regulator of metastatic colonization and validate ANGPT2 as a therapeutic target for a well-defined subset of melanoma patients. SignificanceThis study reveals that tumor cells can be a source of ANGPT2 in the tumor microenvironment and that tumor cell-derived ANGPT2 augments metastatic colonization by protecting tumor cells from oxidative stress.

Purinergic P2Y2 and P2X4 Receptors Are Involved in the Epithelial-Mesenchymal Transition and Metastatic Potential of Gastric Cancer Derived Cell Lines

“…Furthermore, GO analysis revealed that UTP is also affecting cell migration and adhesion pathways, in agreement with the experimental evidence shown in this work. Another noteworthy up-regulated transcript up-regulated is ANGPT2, coding for angiopoietin 2 (Ang-2); Ang-2 has been identified as a metastasis inducer in melanoma [ 64 ] as well as a bad prognosis biomarker in progress and development of colorectal cancer in Japanese [ 65 ] and Chinese [ 66 ] populations. AXL and SMAD2 were also identified as up-regulated transcripts, coding the first for the AXL tyrosine kinase receptor (AXL); whose ligand is named Gas6.…”

Assessing the effect of human dental pulp mesenchymal stem cell secretome on human oral, breast, and melanoma cancer cell lines

“…The significantly augmented growth factors implicated in the progression of A-375 in the present study were Ang-2, EGF, PDGF-BB, TGF-α. Ang-2 has been shown to augment metastatic potential in melanoma ( Abdul Pari et al, 2020 ). Augmented EGF levels have been shown to increase the risk of metastasis in melanoma ( Bracher et al, 2013 ).…”

Abnormal sialylation and fucosylation of saliva glycoproteins: Characteristics of lung cancer-specific biomarkers

“…These proteins can make tumor cells proliferate and activate cell surface growth factor. For instance, the ANGPT-TIE pathway expressed in all tissues acts as an angiogenesis switch in tumors and participates in tumor metastasis and lymphangiogenesis, while ANGPT1 or ANGPT2 have been shown to promote tumorigenesis and tumor malignancy ( Huang et al., 2010 ; Pari et al., 2020 ). Nucleus RTKs (17) are found in most tissues except the lung, and secretory RTKs (20) are detected in the lungs, salivary glands, and pancreas.…”