Cancer remains one of the leading causes of death globally. Metastasis, the spread of cancer to distant sites in the body, is the primary cause of cancer deaths.

It is characterized by cancer cells breaking away from the primary tumor and invading surrounding tissues, blood vessels, and lymph nodes to form new tumors. While the process of metastasis is not entirely understood, there is an increasing amount of evidence indicating that cholesterol plays a critical role.

This article explores the impact of cholesterol on cancer metastasis and the potential therapeutic opportunities that could be developed to combat it.

Cholesterol Metabolism and Cancer

Cholesterol is an essential component of all mammalian cell membranes and serves as a precursor for the synthesis of steroid hormones and bile acids.

Cholesterol metabolism has long been linked to the development of several metabolic disorders, including cardiovascular diseases and type 2 diabetes. However, more recently, there has been growing evidence concerning the role of cholesterol metabolism in cancer development and progression, including metastasis.

Studies have suggested that cancer cells alter cholesterol metabolism to support their growth and division.

For instance, tumor cells can upregulate the expression of the low-density lipoprotein (LDL) receptor family to increase the uptake of circulating cholesterol. They also increase their own synthesis of cholesterol by upregulating the activity of HMG-CoA reductase, a key enzyme that regulates cholesterol synthesis.

Additionally, several signaling pathways that are critical for cancer progression, such as the AKT/mTOR pathway and the Wnt/β-catenin pathway, have been directly or indirectly linked to cholesterol metabolism.

The Role of Cholesterol in Cancer Metastasis

Emerging evidence has linked cholesterol metabolism to cancer metastasis, and this connection is rapidly gaining attention in cancer research.

Cholesterol metabolism has been shown to play a crucial role in multiple steps of the metastatic process, including the escape of cancer cells from the primary tumor, their circulation in the bloodstream, and their establishment at distant sites.

Cholesterol has been found to be essential for the formation of lipid rafts, specialized regions in the plasma membrane that are enriched in cholesterol, sphingolipids, and certain proteins.

These structures facilitate the clustering of signaling molecules and receptors, enabling cells to respond more efficiently to external stimuli. Recent studies have shown that cancer cells rely on these lipid rafts for their survival and maintenance of their metastatic potential.

In particular, metastatic cancer cells are known to undergo a process called epithelial-mesenchymal transition (EMT), whereby they change their characteristics to become more motile and invasive. EMT has been linked to the formation of lipid rafts in cancer cells. Inhibition of cholesterol synthesis or depletion of lipid rafts was found to decrease the motility and invasiveness of cancer cells, suppressing cancer metastasis.

Another way in which cholesterol is thought to contribute to cancer metastasis is through its role in the immune response. The immune system plays a critical role in identifying and eliminating cancer cells that have spread to distant sites.

However, some cancer cells can evade the immune system by upregulating the expression of programmed death-ligand 1 (PD-L1), a protein that binds to the programmed death-1 (PD-1) receptor on immune cells to suppress their activity. Recent studies have suggested that cholesterol metabolism influences the PD-L1 expression in cancer cells. Specifically, inhibition of cholesterol synthesis suppresses the expression of PD-L1, making cancer cells more vulnerable to immune attack.

Therapeutic Opportunities for Cancer Metastasis

The mounting evidence linking cholesterol metabolism to cancer metastasis has stimulated considerable interest in developing therapies targeting this metabolic pathway.

One possible therapeutic target is HMG-CoA reductase, the enzyme that regulates cholesterol synthesis. Several inhibitors of this enzyme, such as statins, are already in clinical use for the treatment of hypercholesterolemia and cardiovascular disease.

Recent studies have shown that statins can also exert anti-tumor effects by suppressing cancer cell proliferation, invasion, and metastasis. Furthermore, statin treatment has been shown to improve the outcomes of patients with certain types of cancer, including breast, prostate, and colorectal cancer.

Other potential targets for cholesterol metabolism-based therapies include the LDL receptor family, which can be targeted using specific antibodies or small molecules, and the mevalonate pathway, which is responsible for the synthesis of various intermediates that are necessary for cell proliferation and survival. The development of such therapies will require a better understanding of how cholesterol metabolism interacts with other signaling pathways that are critical for cancer progression.

Conclusion

In conclusion, the impact of cholesterol metabolism on cancer progression, including metastasis, is an area of intense research. Cholesterol is an essential component of cell membranes, providing structural and signaling functions.

However, it has also been implicated in several metabolic disorders and cancer development and progression. The evidence linking cholesterol metabolism and cancer metastasis is rapidly expanding, with lipid rafts and immune modulation being among the mechanisms involved.

Targeting cholesterol metabolism could provide new therapeutic opportunities for preventing or treating cancer metastasis, although more research and clinical trials are required to fully evaluate their effectiveness.