The ALK1-Smad1/5-ID1 pathway participates in tumour angiogenesis induced by low-dose photodynamic therapy

Photodynamic therapy (PDT) is an effective and low-invasive tumour therapy. However, it can induce tumour angiogenesis, which is a main factor leading to tumour recurrence and metastasis. Activin receptor-like kinase-1 (ALK1) is a key factor regulating angiogenesis. However, it remains unclear whether ALK1 plays an unusual role in low-dose PDT-induced tumour angiogenesis. In the present study, human umbilical vein endothelial cells (HUVECs) co-cultured with breast cancer MDA-MB-231 cells (termed HU-231 cells) were used to construct an experimental model of tumour angiogenesis induced by low-dose PDT. The viability, and the proliferative, invasive, migratory, as well as the tube-forming ability of the HU-231 cells were evaluated following low-dose PDT. In particular, ALK1 inhibitor and and an adenovirus against ALK1 were used to further verify the role of ALK1 in low-dose PDT-induced tumour angiogenesis. Moreover, the expression of ALK1, inhibitor of DNA binding 1 (ID1), Smad 1, p-Smad1/5, AKT and PI3K were detected in order to verify the underlying mechanisms. The findings indicated that low-dose PDT enhanced the proliferative ability of the HU-231 cells and reinforced their migratory, invasive and tube formation capacity. However, these effects were reversed with the addition of an ALK1 inhibitor or by the knockdown of ALK1 using adenovirus. These results indicated that ALK1 was involved and played a critical role in tumour angiogenesis induced by low-dose PDT. Furthermore, ALK1 was found to participate in PDT-induced tumour angiogenesis by activating the Smad1/5-ID1 pathway, as opposed to the PI3K/AKT pathway. On the whole, the present study, for the first time, to the best of our knowledge, demonstrates that ALK1 is involved in PDT-induced tumour angiogenesis. The inhibition of ALK1 can suppress PDT-induced tumour angiogenesis, which can enhance the effects of PDT and may thus provide a novel treatment strategy for PDT.