Autophagy provides a conceptual therapeutic framework for bone metastasis from prostate cancer

Abstract

Prostate cancer is a common malignant tumor, which can spread to multiple organs in the body. Metastatic disease is the dominant reason of death for patients with prostate cancer. Prostate cancer usually transfers to bone. Bone metastases are related to pathologic fracture, pain, and reduced survival. There are many known targets for prostate cancer treatment, including androgen receptor (AR) axis, but drug resistance and metastasis eventually develop in advanced disease, suggesting the necessity to better understand the resistance mechanisms and consider multi-target medical treatment. Because of the limitations of approved treatments, further research into other potential targets is necessary. Metastasis is an important marker of cancer development, involving numerous factors, such as AKT, EMT, ECM, tumor angiogenesis, the development of inflammatory tumor microenvironment, and defect in programmed cell death. In tumor metastasis, programmed cell death (autophagy, apoptosis, and necroptosis) plays a key role. Malignant cancer cells have to overcome the different forms of cell death to transfer. The article sums up the recent studies on the mechanism of bone metastasis involving key regulatory factors such as macrophages and AKT and further discusses as to how regulating autophagy is crucial in relieving prostate cancer bone metastasis.

Fig. 1. The basic metastatic sites and pathways of PC and the vicious circle of osteolytic metastasis.

Prostate cancer mainly metastases to the bone, but some tumor cells also spread through the blood to the viscera, such as the lung, liver, and brain. In addition, PC can also develop direct spread and lymph node metastasis. Parathyroid hormone-related peptides secreted by tumor cells are the major stimulators of osteoclast formation. Additionally, cancer cells also generate other factors, the formation of which promote osteoclasts, including prostaglandin E2 (PGE2), interleukin, macrophage colony-stimulating factor (M-CSF), and tumor necrosis factor. These factors increase the expression of nuclear factor-KB ligand receptor activators (RANKL), which acts on preosteoclast to induce bone resorption and osteoclast formation directly. Bone resorption releases factors including platelet-derived growth factor (PDGF), fibroblast growth factors (FGFs), insulin-like growth factors (IGFs), bone morphogenetic proteins (BMPs), and transforming growth factor b (TGF-b), which can enhance the parathyroid hormone–related peptide production through cancer and growth factors, thereby promoting tumor growth. Tumor growth and bone destruction are further increased because of the symbiotic connection between tumor growth and bone destruction.

Fig. 2. Different factors that inhibit or promote bone metastasis from PC.

Influence of different signaling pathways and drugs on bone metastasis from PC.

Fig. 3. The mechanism of metastasis via blood in advanced bone metastasis from PC.

Bone metastasis from PC mainly occurs via blood, where multiple signaling pathways are involved. Focus on the AKT signaling pathway, which has a remarkable relationship with autophagy, and TGF-β signaling pathway, which can induce EMT formation and release Smad protein to promote tumor metastasis.