Macrophages Contribute to the Progression of Infantile Hemangioma by Regulating the Proliferation and Differentiation of Hemangioma Stem Cells

Abstract

Macrophage infiltration has been implicated in infantile hemangioma (IH), the most common tumor of infancy. However, the exact role of macrophages in IH remains unknown. This study aims to clarify the functional significance of macrophages in the progression of IH. The distribution of macrophages in human IH was analyzed, and our results revealed that polarized macrophages were more prevalent in proliferating IHs than in involuting IHs, which was consistent with the increased macrophage-related cytokines in proliferating IHs. In vitro results further demonstrated that polarized macrophages effectively promoted the proliferation of hemangioma stem cells (HemSCs) and suppressed their adipogenesis in an Akt- and extracellular signal-regulated kinase 1/2 (Erk1/2)-dependent manner. Moreover, M2- but not M1-polarized macrophages promoted the endothelial differentiation of HemSCs. Furthermore, mixing macrophages in a murine hemangioma model elevated microvessel density and postponed fat tissue formation, which was concomitant with the activation of Akt and Erk1/2 signals. Cluster analysis revealed a close correlation among the macrophage markers, Ki67, vascular endothelial growth factor (VEGF), p-Akt, and p-Erk1/2 in human IH tissues. Collectively, our results suggest that macrophages in IH contribute to tumor progression by promoting the proliferation and endothelial differentiation while suppressing the adipogenesis of HemSCs. These findings indicate that targeting the infiltrating macrophages in IH is a promising therapeutic approach to accelerate IH regression.

Infiltration of M2‐polarized macrophages in infected lymphatic malformations: possible role in disease progression

“…Macrophages play an important role in inflammatory diseases, immunological diseases and tumours . Our previous studies reported that macrophages are also involved in the development of infantile haemangioma . We here report that macrophages might also contribute to the progression of another vascular anomaly, LMs.…”

Association of ATF4 Expression With Tissue Hypoxia and M2 Macrophage Infiltration in Infantile Hemangioma

“…24 Our recent studies have unveiled that macrophages contribute to IH progression via promoting the angiogenic process. 14,15 Notably, a recent study provides evidence that hypoxia could upregulate ATF4 expression in macrophages. 25 On the other hand, there is evidence showing that ATF4 in breast cancer cells is capable of promoting macrophage recruitment via secretion of M-CSF, thereby facilitating tumor angiogenesis.…”

“…The diagnosis and classification of each IH case was established according to clinical presentation and histopathological features, as we described previously. 15 …”

“…[13][14][15] M2-polarized macrophages can not only promote the proliferation and endothelial differentiation but also suppress the adipogenesis of HemSCs. 15 Macrophage colony-stimulating factor (M-CSF) is a wellknown key regulator for the differentiation, polarization, and survival of macrophages among a broad spectrum of pathologies. [16][17][18] However, whether hypoxia, a wellestablished driving force in IH progression, may affect or regulate macrophages in IH remains largely unknown.…”

β-Adrenoceptor Blockade for Infantile Hemangioma Therapy: Do β₃-Adrenoceptors Play a Role?

“…Macrophages from the M2 group may be involved by promoting the proliferation of aberrant cells [37], which in turn promote differentiation of tumor cells into endothelial cells and pericytes [38]. On the other hand, the regressive phase seems to include the participation of macrophages from the M1 group [39].…”