The genetic circle has also been popular recently. A few days ago, scientists discovered that the powerful cancer-causing gene ALK was responsible for managing human weight. Today, Rockefeller University Sohail F. The Tavazoie team has another surprising finding: The APOE4 gene, the strongest associated with Alzheimer’s disease, may inhibit the metastasis of melanoma and significantly increase patient sesame times.
This two-sided feature of APOE is a complete surprise.
This is really “the blessing of the good, the blessing of the curse”, or “the fish and the bear’s palm can not be both.”
The elegant Sohail F. Tavazoie
The Tavazoie team’s research is published today in the top journal Nature Medicine. Tavazoie believes that his findings are the first to confirm that the congenital genotypes inherited from parents (acquired by non-acquired mutations) can affect the progression and prognosis of malignant tumors.
For the implications of this study, Tavazoie believes that perhaps the APOE genotype can be used as a marker for predicting prognosis and immune therapy responses in melanoma patients, and that a prospective clinical study is needed around this conclusion.
“Patients often ask, ‘Why am I so unlucky?’ Why does my cancer spread? ‘As doctors, we haven’t had an answer. “Tavazoie said, “Our study provides an explanation. “
Screenshot of the first page of the paper
Metastasis is the leading cause of death from cancer.
An important point of view on cancer metastasis is that as cancer develops, new genetic variants continue to emerge, which has allowed cancer cells to metastasize. Unfortunately, scientists have spent decades searching for mutations in the gene responsible for cancer metastasis, but have yet to find such a gene.
As early as 2012, when the Tavazoie team studied the driving forces of cancer metastasis, they found that lipoprotein E (APOE) appeared to inhibit the metastasis of melanoma. But one of the questions that bothers them is, although melanoma inhibits the expression of APOE in the course of development, normal cells outside the tumor can also express APOE, why does melanoma still metastasize?
When they thought that There were three variants of APOE, they were suddenly open-minded.
Tavazoie speculates that different APOE proteins may have different regulatory effects on tumor progression.
I’m sure you’re certainly familiar with the APOE protein, which is related to Alzheimer’s disease, but also to the metabolism and immunity of the human body.
APOE can be divided into three subtypes, APOE2, APOE3 and APOE4, of which APOE4 is most closely related to Alzheimer’s disease, while APOE2 can reduce the risk of Alzheimer’s disease in carriers, APOE3 is the common type. There are differences in the binding and activation of these three subtypes and receptors.
Given the relationship between APOE and immunity, as well as the different subtypes, the Tavazoie team decided to explore the effects of a different subtypes of APOE on cancer progression.
To test these assumptions, Tavazoie and his colleagues found mice whose APOE genes were replaced by three APOE genes, and explored the effects of different APOE genotypes on the development of primary melanin.
They found that aPOE4 mice had significantly smaller tumorsizes and a median tumor size in APOE3 mice than APOE2 mice. The melanoma metastasis experiment also found the same conclusion: APOE4 mice had less metastasis than APOE2.
These two small experiments initially confirmed that the mice’s own different APOE genotypes did have different effects on the progression of melanoma.
Effect of APOE genotype on primary tumor
So what exactly affects the progression of melanoma?
To figure this out, you have to look back at previous research. Scientists have found that APOE can regulate the immune response under a variety of different conditions. Specifically in cancer, APOE can enhance anti-tumor immunity by regulating the bone marrow immune cell population.
If so, it means that the three different subtypes of APOE have different effects on the immune system.
It is not difficult to find out whether there is a difference in immune abilities in three different APOE subtypes, directly on the flow cytometer.
The analysis showed that the tumor of APOE4 mice had increased the recruitment capacity of CD45-white blood cells compared to APOE2 mice, while the proportion of Ly6G-granulocytes with immunosuppressive bone marrow-derived inhibitory cells (G-MDSCs) and tumor-related macrophages was lower in APOE4 mice.
In addition, anti-tumor-resistant immune cells such as natural killer cells (NK) and CD8-T cells not only increased in APOE4 mice, but also increased the activity of these cells, such as increased expression of granulase B and interferon-pyridine.
Figure a-f: APOE4 mice have a full immunity over APOE2 mice
Based on the above data, the researchers believe that APOE regulates the abundance and functionalstate of the tumor immune microenvironment, and that APOE4 does induce a stronger anti-tumor immune response than APOE2.
In doing so, the Tavazoie team has seen what they want most. But they also had to prove that there was a causal relationship between the phenomena they observed, rather than a simple correlation.
To solve this problem, they directly removed CD4-/CD8-T cells from mice, resulting in no difference in tumor progression in APOE2 mice and APOE4 mice. This suggests that there is a real causal relationship between changes in APOE and anti-tumor immunity.
There is a causal relationship between changes between APOE and anti-tumor immunity
So far, the Tavazoie team has nearly perfectly demonstrated in mice that APOE4 enhances the anti-tumor capability of mice and inhibits the progression of tumors in mice. So can this conclusion cross from mice to the human body? It is also relevant to the value of this research.
The quickest way to solve these problems is to study the data in the TCGA database and analyze the prognosis of melanoma patients with different APOE subtypes.
Tavazoie and he first analyzed the proportion of APOE2 and APOE4 subtypes in melanoma patients, as well as the proportion of normal populations, with no difference. This means that APOE2 and APOE4 do not promote cancer per se.
However, the different subtypes of APOE are actually associated with the prognosis of melanoma patients.
The median survival of patients with APOE2 was 2.4 years, the median survival of APOE3 pure-fit patients was 5.2 years, and the median survival of patients with APOE4 was 10.1 years.
This figure is so surprising.
The researchers then validated the findings in a separate study.
APOE subtype and prognosis for patients
At the same time, the researchers thought that immunotherapy had rewritten the history of melanoma treatment, and that the effect of APOE on patients’ prognosis was also associated with immunity. So the different subtypes of APOE have different effects on immunotherapy?
Both mouse studies and the analysis of existing immunotherapy data were found to have the longest survival time for APOE4 carriers and the shortest survival time for APOE2 carriers. The APOE subtype does have the ability to predict patients’ response to immunotherapy.
Effect of APOE subtype on immunotherapy effect
Overall, Tavazoie believes their study proves that “congenital genetic variation affects the progression of malignant tumors and the prognosis of patients.”
In addition, if prospective studies can reproduce the prediction of immune therapy prognosis for different subtypes of APOE, then the APOE gene can be used as a predictable marker of recurrent metastasis and death risk in melanoma patients. If similar phenomena could be found in more other cancers, the study would be even more valuable.
Finally, after reading this study, how many people remembered the genetic variants (HbS and HbA) associated with sickle anemia and malaria.