Cancer therapy that targets the Hedgehog signaling pathway considering the cancer microenvironment

Recently, the cancer microenvironment (CME) has received significant attention. At the local site of the tumor, cancer progression is affected by secreted cytokines and conditions derived from the CME and stimulation by cancer-induced cytokines in an autocrine manner. The CME is characterized by various types of conditions, such as hypoxia, inflammation stimulation, and angiogenesis, and contains various components, such as reactive oxygen species, cancer-associated fibroblasts, infiltrated immune cells, exosomes, and cancer stem cells (CSCs). These conditions and components complicate the progression of cancer. The Hedgehog (HH) signaling pathway is a morphogenesis signaling pathway that is reactivated in some cancers. In these cancers, reactivated HH signaling is involved in the induction of the malignant phenotype. HH signaling is also activated under hypoxic conditions and is considered to be strongly correlated with the CME, including the induction of cancer fibrosis and maintenance of CSCs. The aim of the present review was to elucidate a cancer therapy that targets HH signaling by considering the CME, particularly focusing on hypoxia.