Release date: 2016-12-27
Professor Julio A. Aguirre-Ghiso
According to statistics, 90% of cancer-related deaths are caused by tumor metastasis. In most people's view, the metastasis process of tumors is probably like this: some cells undergo mutations during the process of proliferation, leading to uncontrolled cell growth and formation of tumors; in the process of continuous cell division and proliferation, new gene mutations continue Accumulation, until some day, some tumor cells accidentally acquired genetic mutations related to metastasis, tumor cells showed invasiveness; they spread along the blood vessels and transferred to the appropriate organs for cancer.
The "cancer moon landing plan" that is currently being carried out in various countries is also based on this theory. Everyone wants to understand, overcome and predict the drug resistance in cancer treatment by deep sequencing of the primary lesion. Of course, if the cancer cells that form metastases in other tissues and organs are from the tumor tissue that we sequenced and sampled, it would be fine. However, since 2002, studies have shown that (1-4), cancer cells leave the primary lesions at the very early stage of tumor formation, and they are independently camped on other tissues and organs. This means that I am afraid I will not talk about it.
However, the academic community has not always been aware of the secret behind the ultra-early transfer of tumor cells, so that there is no way to find a countermeasure. Finally, on December 14, a team of professors Julio A. Aguirre-Ghiso from the Icahn School of Medicine at Mount Sinai (ISMMS) (5) and the University of Regensburg, Germany (University of Dr. Christoph A. Klein (6) of Regensburg, co-published two articles online in Nature, and for the first time clarified the mechanism by which cancer cells spread early.
Surprisingly, they also found that cancer cells that spread out early in the tumor formation were more capable of colonizing the metastatic lesion than cancer cells that were spread after the tumor was formed. This has completely subverted our long-standing understanding of tumor metastasis. This means that we should focus more on the early stages of tumorigenesis and study mature tumors, which may not solve the problem fundamentally. Cyrus M. Ghajar of the Fred Hutchinson Cancer Research Center and Mina J. Bissell of the Lawrence Berkeley National Laboratory jointly commented on this important research advancement in Nature (7).
Make an inappropriate analogy. When we classify startup companies, we often use the words Ali, Tencent, and Huada to classify some companies. The founders and core teams of these startups mostly started their business when Ali, Tencent and Huada were in a climate, so these companies have more or less the shadows of Ali, Tencent and Huada. We can even see you. When you are in the company, say a few of the features they might have.
Dr. Christoph A. Klein (orange tie)
But when there were only a dozen people in Ali, Tencent and Huada, they left the entrepreneurs, and the companies they founded later, we could not judge according to Ali, Tencent and Huada. And these people, if they succeed in business, often the latecomers of each department are incomparable. The reason is simple, but the scientists have been studying for more than a decade.
How did the team of Professor Aguirre-Ghiso and Dr. Klein discover the secret?
First, as early as 2003, Dr. Klein's team found in breast cancer research that the genetic mutations in breast cancer cells disseminated in the bone marrow were much less than those in the original lesions (2). This means that these diffused cancer cells come out earlier and evolve independently.
They also found more evidence that the spread of cancer cells is actually accompanied by the whole process of tumor development. For example, 20%-30% of cancer cells diagnosed as "non-invasive" breast cancer patients can be found in disseminated cancer cells (8). Another 8% of "non-invasive" breast cancers are far from the breast (9). Moreover, in all cancer patients, about 5% of patients can not find the primary lesion. This evidence at least indirectly proves that cancer cells have spread out in the early stages of tumor formation.
In breast cancer model mice driven by oncogene Her2 overexpression, scientists also found that when mice were 4 weeks old, there were diffuse cancer cells in the bone marrow of mice, and the oncogene in mice at this time. Her2 was also expressed soon. And the breast cancer at this time can only be seen by electron microscopy, and it will develop into a palpable tumor in the next 14 weeks (1). This is clearly a direct proof that there is indeed a very early spread of cancer cells.
Breast cancer cells under electron microscope (Figure: ANNE WESTON/WELLCOME IMAGES)
In the early days, the spread of cancer cells was not aggressive, and there was no blood vessels in this area where the tumor was about to grow. How did these cancer cells pass through heavy cells and enter the blood vessels to reach the bone marrow?
Obviously, the team of Professor Aguirre-Ghiso and the team of Dr. Klein, the mission at this time is to find the mechanism for the early spread of cancer cells. Of course, this basic study can only be done in model mice, and they also chose breast cancer model mice driven by the oncogene Her2 overexpression.
Hedayatollah Hosseini, the project leader of Dr. Klein's team, took out the epithelial cells of the mouse mammary ducts before the mice grew to 9 weeks, and analyzed the gene expression of epithelial cells (6). Hosseini found that progesterone caused the spread of cancer cells. There are two types of mammary ductal epithelial cells, one with a progesterone receptor and one without. Epithelial cells with progesterone receptors, under the stimulation of progesterone, secrete two specific proteins (WNT4 and RANKL), which are the two proteins that induce cells without progesterone receptors to detach from the mammary duct and eventually enter marrow.
However, Hosseini found that as the tumor volume increased, Her2 protein accumulated, the role of progesterone was inhibited, and the tumor switched from a diffused state to a proliferative state.
Early tumors are not yet obvious (7). a, Hosseini et al found that the progesterone stimulates progesterone receptor epithelial cells (brown dots) to secrete WNT4 and RANKL proteins, promoting epithelial cells without progesterone receptors (yellow dots, blue cells) Remove the mammary duct and enter the bone marrow; b, Harper et al. found that the Her2 protein causes an increase in WNT protein, and a large number of WNTs inhibit the formation of p38 protein, resulting in the connection of mammary ductal epithelial cells (red) without progesterone receptors to surrounding cells. Loose, break away from the tissue and enter the bone marrow.
Kathryn L. Harper, project leader of the Aguirre-Ghiso team, found another mechanism in parallel experiments (5). The expression of Her2 protein in mice activates WNT protein, which greatly increases WNT; increased WNT inhibits the expression of p38 protein; and the role of this p38 protein is to strengthen the relationship between cells, so that the cells do not leave the mammary duct. Since the p38 protein is inhibited, the mammary duct epithelial cells enter the bone marrow in the form of early cancer cells.
The two teams also found a strange phenomenon. When early-spreading cancer cells and late-spreading cancer cells were placed in the mammary ducts, early-spreading cancer cells were less able to form new lesions than late-staged cancer cells. But the ability to form lesions at the metastatic site is exactly the opposite.
However, this mechanism is currently found in Her2-driven breast cancer, and whether this phenomenon is present in other types of cancer requires further research, but they have laid the groundwork for subsequent research. In cancers (skin and pancreatic cancer) where early cancer cell spread has been observed, scientists can determine the relevant mechanisms as soon as possible.
Advanced tumors also have cancer cells that spread to the bone marrow, but these cancer cells are clearly less capable of colonizing the bone marrow than cancer cells that spread early (7).
Hosseini has confirmed in the human body that there is a significant difference in molecular level between early-spread cancer cells and cancer cells of the primary lesion. Therefore, Ghajar and Bissell said that researchers should separate enough early-spread cancer cells from patients as soon as possible and conduct in-depth research and analysis.
What is even more worrying is that the current targeted therapy is developed using the information of the primary lesion, which is very likely to cause the early spread of cancer cells to escape the drug, which may also be cancer easily recurring and One of the underlying causes of drug resistance.
In addition, this poses a challenge to our cancer screening system. If the spread of cancer cells is accompanied by the whole process of tumor formation and formation, if the characteristics of early-spreading cancer cells are not understood, what is the significance of early cancer screening? After all, this diffusion process should be much earlier than the early stages of cancer we now define.
"When the vast majority of patients are diagnosed with cancer, the cancer cells have actually spread," Professor Aguirre-Ghiso said in an interview with STAT. "This is really bad news. But we still have the opportunity to intervene because of this spread out of cancer." The cells don't immediately attack." Aguirre-Ghiso's team is looking for a switch that controls early spread out of cancer cells.
For women carrying the Her2 mutation (25% of breast cancer patients carry the mutation), the researchers suggested in an interview with COSMOS that they can consider regular monitoring of abnormal cells in the blood from the current research progress. Try to find cancer violations as early as possible.
Source: Singularity Network BioTalker
Tissue Box,Napkins Plastic Box,Car Visor Tissue Box,Pu Leather Car Box
YIWU CHUANGCHENG IMPORT&EXPORT CO.,LTD , https://www.tradingsix.com