It may be time to add ‘potential cancer fighter’ to the list of promising benefits of high density lipoprotein (HDL), the carrier of “good cholesterol,” according to research from Cleveland Clinic’s Lerner Research Institute.
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In a series of experiments, Stanley Hazen, MD, PhD, and his team determined that apolipoprotein A1 (apoA1), or the major cardioprotective protein component of HDL, combats metastatic malignant melanoma and lung cancer through multiple pathways. ApoA1 injections not only inhibited tumor growth and progression in experiments with mice, but actually spurred tumor and metastases regression.
Researchers at Cleveland Clinic, including Dr. Hazen; Joseph DiDonato, PhD; Maryam Zamanian-Daryoush, PhD; and Daniel Lindner, MD, PhD, are now poised to translate these findings to therapeutic strategies for the clinical setting.
The apoA1 discoveries are a prime example of advances from the evolving field of cardiooncology. “Cardiovascular disease and cancer are not so disparate in the sense that there are major contributing pathways that operate in concert in both diseases,” says Dr. Hazen, Chair of Cellular and Molecular Medicine, the Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis, and the Leonard Krieger Chair in Preventive Cardiology. “In apoA1, we may have identified an important central player nexus and a possible intervention that works positively to combat both diseases.”
After in vitro studies ruled out a direct effect of apoA1 on tumor cells, the Cleveland Clinic team determined apoA1 instead modulates innate and adaptive immune systems in the host in multiple ways to create a micro-environment that works against cancer development. For example, they demonstrated apoA1 can switch tumor-associated macrophages from an M2 phenotype to a more beneficial M1; can decrease tumor angiogenesis independent of vascular endothelial growth factor pathways; and can increase levels of tumor-killing CD8 T cells circulating in and around a tumor.
Although complexity usually works in cancer’s favor, here it may be a distinct disadvantage.
“The simple elegance of a multipronged approach is that the tumor cell should have a very difficult time in coming up with a solution to negate apoA1 effects,” says Dr. DiDonato, Supervisor of the Cellular and Molecular Medicine Laboratory.
“If apoA1 had a direct effect on the tumor, the tumor could mutate to circumvent apoA1’s direct effect, much like tumors do in response to chemotherapeutic agents that target a single pathway or protein in the tumor cell.” Dr. Hazen says, “In contrast to most chemotherapies, which weaken the immune system and have infection risk as a side effect, apoA1 therapy for these tumors augments the immune system’s functions, harnessing the body’s natural tumor-fighting potential to promote tumor and metastases regression. It’s exciting.”
The investigators observed zero to very limited metastatic melanoma tumor growth in transgenic animals overexpressing apoA1 at approximately twice the normal circulating levels. In further experiments, Dr. Hazen, Dr. DiDonato and their colleagues found palpable tumors regressed 50 percent from their peak volume within one week among animals injected with apoA1, a beneficial result maintained over time.
It remains unknown if apoA1’s anti-inflammatory action is the shared underlying etiology between the benefits of HDL seen in cardiology and potentially now also observed in oncology. “That is the $64,000 question,” Dr. DiDonato says. “What we do know is that inflammation plays a major role, not only in the initiation or establishment of the tumor, but also in the propagation and migration or metastasis of the tumor cells.”
