Targeting HDL in tumor microenvironment: New hope for cancer therapy.

Epidemiological studies have shown that plasma HDL-C levels are closely related to the risk of prostate cancer, breast cancer, and other malignancies. As one of the key carriers of cholesterol regulation, high-density lipoprotein (HDL) plays an important role in tumorigenesis and cancer development through anti-inflammation, antioxidation, immune-modulation, and mediating cholesterol transportation in cancer cells and noncancer cells. In addition, the occurrence and progression of cancer are closely related to the alteration of the tumor microenvironment (TME). Cancer cells synthesize and secrete a variety of cytokines and other factors to promote the reprogramming of surrounding cells and shape the microenvironment suitable for cancer survival. By analyzing the effect of HDL on the infiltrating immune cells in the TME, as well as the relationship between HDL and tumor-associated angiogenesis, it is suggested that a moderate increase in the level of HDL in vivo with consequent improvement of the function of HDL in the TME and induction of intracellular cholesterol efflux may be a promising strategy for cancer therapy.

Involvement of LDL and ox-LDL in Cancer Development and Its Therapeutical Potential.

Lipid metabolism disorder is related to an increased risk of tumorigenesis and is involved in the rapid growth of cancer cells as well as the formation of metastatic lesions. Epidemiological studies have demonstrated that low-density lipoprotein (LDL) and oxidized low-density lipoprotein (ox-LDL) are closely associated with breast cancer, colorectal cancer, pancreatic cancer, and other malignancies, suggesting that LDL and ox-LDL play important roles during the occurrence and development of cancers. LDL can deliver cholesterol into cancer cells after binding to LDL receptor (LDLR). Activation of PI3K/Akt/mTOR signaling pathway induces transcription of the sterol regulatory element-binding proteins (SREBPs), which subsequently promotes cholesterol uptake and synthesis to meet the demand of cancer cells. Ox-LDL binds to the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and cluster of differentiation 36 (CD36) to induce mutations, resulting in inflammation, cell proliferation, and metastasis of cancer. Classic lipid-lowering drugs, statins, have been shown to reduce LDL levels in certain types of cancer. As LDL and ox-LDL play complicated roles in cancers, the potential therapeutic effect of targeting lipid metabolism in cancer therapy warrants more investigation.

Celastrol ameliorates vascular neointimal hyperplasia through Wnt5a-involved autophagy.

Neointimal hyperplasia caused by the excessive proliferation of vascular smooth muscle cells (VSMCs) is the pathological basis of restenosis. However, there are few effective strategies to prevent restenosis. Celastrol, a pentacyclic triterpene, has been recently documented to be beneficial to certain cardiovascular diseases. Based on its significant effect on autophagy, we proposed that celastrol could attenuate restenosis through enhancing autophagy of VSMCs. In the present study, we found that celastrol effectively inhibited the intimal hyperplasia and hyperproliferation of VSMCs by inducing autophagy. It was revealed that autophagy promoted by celastrol could induce the lysosomal degradation of c-MYC, which might be a possible mechanism contributing to the reduction of VSMCs proliferation. The Wnt5a/PKC/mTOR signaling pathway was found to be an underlying mechanism for celastrol to induce autophagy and inhibit the VSMCs proliferation. These observations indicate that celastrol may be a novel drug with a great potential to prevent restenosis.

Autophagy: a killer or guardian of vascular smooth muscle cells.

Vascular smooth muscle cells (VSMCs) is one of the main intracellular components of the blood vessel wall. The abnormalities of VSMCs participate in the development of cardiovascular diseases such as atherosclerosis, hypertension, and restenosis, especially the formation and stability of atherosclerotic plaques. Autophagy is involved in the regulation of proliferation, migration and phenotype switching of VSMCs, which in turn affects the pathological process of atherosclerosis. However, the autophagy of VSMCs has a dual effect on cells survival. Autophagy is induced in VSMCs by various stimuli such as 7-ketocholesterol (7-KC), unsaturated lipid peroxidation-derived aldehyde and excess free cholesterol, thereby promoting VSMCs survival and stabilising atherosclerotic plaque. Conversely, autophagy caused by factors such as osteopontin (OPN), angiotensin II (Ang II) and nicotine can accelerate the death of VSMCs, further accelerating atherosclerotic lesions. In addition, mitophagy and lipophagy as selective autophagy are also involved in the outcome of VSMCs as well as progression of atherosclerotic lesion. Currently, there are only a few drugs available to induce VSMCs autophagy, such as atorvastatin, telmisartan and so on. Due to the important role of VSMCs autophagy in the progression of atherosclerosis plaques, drugs that directly target autophagy of VSMCs are urgently needed to be developed.