Release date: 2017-11-13
The cancer cells are really too tenacious, and the singular cakes feel that there must be a motto inside them - "killing me will only make me stronger." Even though we have many treatments, we fight cancer cells. All can only talk about the staged victory. Because these bad guys always have ways to escape the sanctions, hide in other corners of the body, and wait for the comeback. Clinical investigations have shown that breast cancer still retains the possibility of recurrence after 20 years of cure.
It stands to reason that these cancer cells that have escaped a catastrophe are not dead, and there should be no fighting power. In many cancers, researchers have observed damage to cancer cell mitochondrial DNA (mtDNA) and loss of entire mtDNA copies after treatment [1-3]. After hormone therapy (eg, tamoxifen), mtDNA in estrogen receptor (ER)-positive breast cancer cells is reduced by 70%-90%. These cancer cells have slower energy metabolism. Although they have not died yet, they have no strength to make waves and start "hibernation."
Who is owing to wake up cancer cells? A recent study published in the Proceedings of the National Academy of Sciences (PNAS) captured the murderer [4].
The research team led by Dr. Jacqueline Bromberg of the Sloan Kettering Cancer Research Center (MSK) found that the microenvironment of "hibernating" cancer cells secretes exosomes containing mtDNA, giving cancer cells "snow in the snow"! Scientists saw that the exosome carrying the entire set of mtDNA "fitted" with the mitochondria in the cancer cells, and then the miracle happened - the mitochondria returned to normal work, and the cancer cells woke up and woke up! These cancer cells have resumed proliferation and metastasis, and even more terrifying is the resistance to hormone therapy.
On the right is Dr. Jacqueline Bromberg
What is Exosomes? It is a small vesicle secreted by cells to the outside of the cell, carrying important information such as various proteins, lipids, DNA and RNA of the mother cell. This up-and-coming talent that caught the attention of researchers at the end of the last century has brought us many surprises in the fields of cancer detection, activation of immunity and treatment of diseases. Before the study, no researchers found that exosomes could actually hold a full set of mtDNA [5].
The researchers analyzed exosomes in a batch of plasma samples and found that 86% (19/22) of anti-hormone-treated patients with metastatic recurrence detected high levels of mtDNA. In healthy individuals, early patients, and untreated advanced patients, only very few, or no mtDNA was detected at all.
That is to say, exosomes containing mtDNA are only specifically present in patients with metastasis recurrence of anti-hormone therapy.
Right, it can be seen that mtDNA can only be detected in exosomes of patients with metastatic breast cancer with anti-hormone therapy.
Where did these exosomes containing mtDNA come from?
The researchers transplanted human ER-positive breast cancer cells to mice and subsequently treated them with tamoxifen. A few months after the tumor disappeared, some mice developed metastasis and recurrence and developed resistance to hormone therapy. This is consistent with clinical manifestations of patients with breast cancer metastasis and recurrence.
The researchers obtained a surprising result in detecting these resistant cancer cells. Cancer cells come from humans, and their nucleus naturally has human DNA, but mitochondrial DNA is from mice! That is to say, these exosomes containing mtDNA are likely to be from surrounding tissues of cancer cells.
Almost all mtDNA comes from the host (mouse)
Through extensive screening, the researchers determined that these mtDNAs are derived from tumor-associated fibroblasts (CAFs) in the tumor microenvironment, which is the most important type of cells in the microenvironment.
So what effect does these mtDNA from exosomes have on dormant cancer cells?
The researchers delivered weekly mtDNA-containing exosomes secreted by tumor fibroblasts to sleeping cancer cells for a total of 4 weeks. After another 6 weeks, the sleeping cancer cells "wake up" and began to repopulate. It can be seen under electron microscopy that these foreign exosomes have "fitted" with the mitochondria of cancer cells 48 hours after delivery.
The researchers also performed this experiment in mice. After the mice were injected with dormant cancer cells, 60% of the mice developed larger tumors six months after they were injected with exosomes produced by normal cells. In contrast, mice injected with exosomes secreted by cells knocked out by mtDNA showed only very small tumors in two.
This is enough to prove that the mtDNA contained in the exosomes can awaken dormant cancer cells, leading to cancer recurrence.
In addition to recurrence, the researchers also found that cancer cells waking up in this way are resistant to hormone therapy! Subsequent experiments also showed that exosomes produced by CAFs were sent to untreated cancer cells, and after hormone therapy, cancer cells were acquired drug resistance; and the cancer cells were sent to exfoliate cells that knocked out mtDNA. Body, it still can not resist the power of hormones.
A study published by Dr. Jacqueline Bromberg's team found that microbubbles secreted by the tumor microenvironment will transmit miRNAs to cancer cells [6], activating the corresponding signaling pathways in cancer cells [7], leading to drug resistance. In addition, some studies suggest that changes in mtDNA mutations, deletions, and copy number are themselves associated with the development of resistance [8-9].
As for the exosomes, they are so conscious of how mtDNA is packaged and how it is released. How to fit the mitochondria of cancer cells, this should be left to future generations to study.
Dr. Bromberg said the study opened up a promising area of ​​research, with a focus on patients who have successfully managed breast cancer development, and regularly screened for exosomes containing mitochondrial DNA in the blood to predict whether the cancer will recur. Another part of the work can try to prevent cancer recurrence by preventing the production of this exosome. And for other cancers that are “dormantâ€, such as prostate cancer and melanoma, this study may also have some implications [5].
Source: Singularity Network (micro signal geekheal_com)
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