Heme Oxygenase-1 Has a Greater Effect on Melanoma Stem Cell Properties Than the Expression of Melanoma-Initiating Cell Markers

Abstract

Melanoma-initiating cells (MICs) contribute to the tumorigenicity and heterogeneity of melanoma. MICs are identified by surface and functional markers and have been shown to display cancer stem cell (CSC) properties. However, the existence of MICs that follow the hierarchical CSC model has been questioned by studies showing that single unselected melanoma cells are highly tumorigenic in xenotransplantation assays. Herein, we characterize cells expressing MIC markers (CD20, CD24, CD133, Sca-1, ABCB1, ABCB5, ALDHhigh) in the B16-F10 murine melanoma cell line. We use flow cytometric phenotyping, single-cell sorting followed by in vitro clonogenic assays, and syngeneic in vivo serial transplantation assays to demonstrate that the expression of MIC markers does not select CSC-like cells in this cell line. Previously, our group showed that heme-degrading enzyme heme oxygenase-1 (HO-1) can be upregulated in melanoma and increase its aggressiveness. Here, we show that HO-1 activity is important for non-adherent growth of melanoma and HO-1 overexpression enhances the vasculogenic mimicry potential, which can be considered protumorigenic activity. However, HO-1 overexpression decreases clone formation in vitro and serial tumor initiation in vivo. Thus, HO-1 plays a dual role in melanoma, improving the progression of growing tumors but reducing the risk of melanoma initiation.

Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies

“…75 Previous studies revealed CSCs and adult stem cells share multiple signatures, including the surface markers CD133, CD44, CD24, CD26, CD166, and EPCAM, and intracellular proteins like ALDH1. [76][77][78] Additionally, CSCs and stem cells also share similar developmental related signaling pathways, such as WNT, NOTCH, and Hedgehog (Hh). 29,79 Like normal stem cells, CSCs propagate through asymmetric division, which produces one daughter cell that remains a CSC and one committed progenitor cell that differentiates into a non-CSC.…”

Targeting drug‐tolerant cells: A promising strategy for overcoming acquired drug resistance in cancer cells

“…They can differentiate into heterogeneous tumor cells, which is considered to be one of the root causes of tumor development, recurrence and metastasis, and drug resistance 63,83 . Previous studies reveal that CSCs and adult stem cells share multiple signatures, including the surface markers of CD133, CD44, CD24, CD26, CD166, and EPCAM, and intracellular proteins like ALDH1 84–88 . Additionally, CSCs and stem cells also share similar development‐related signaling pathways, such as WNT, NOTCH and Hedgehog (Hh) 89,90 .…”

“… 63 , 83 Previous studies reveal that CSCs and adult stem cells share multiple signatures, including the surface markers of CD133, CD44, CD24, CD26, CD166, and EPCAM, and intracellular proteins like ALDH1. 84 , 85 , 86 , 87 , 88 Additionally, CSCs and stem cells also share similar development‐related signaling pathways, such as WNT, NOTCH and Hedgehog (Hh). 89 , 90 CSCs are characterized by slow proliferation or a quiescent state, thus they become resistant to antiproliferation drugs.…”