Release date: 2016-12-22
Two papers published online by Nature's Icahn School in Mount Sinai and Regensburg University in Germany on December 15 revealed that breast cancer cells with certain molecular changes can spread to other organs even before the primary tumor is formed. Stay silent for a long time and then wake up to form an aggressive, fatal breast cancer metastasis.
The researchers said that their findings in Nature were obtained by conducting experiments in animal models and testing them in human samples. These findings address the secrets of how metastatic breast cancer develops in the absence of primary tumors in this new early tumor transmission and metastasis model. Even researchers say that clinically primary tumors may never form. Both teams have now identified mechanisms that allow cells to spread early in cancer progression and promote metastasis.
1, the Sinai team found that breast cancer can be transferred without primary tumor
In the Sinai study, two changes in breast cancer cells (an open oncogene and a closed tumor suppressor gene) prompted cells to migrate from the breast tissue to the lungs and other parts of the body. There, the cells remain stationary until the growth switch is activated and metastases appear in the lungs.
The study's co-author, Dr. Julio A. Aguirre-Ghiso of Mount Sinai, said: "This study provides insight into the mechanisms of early cancer transmission and may shed light on some unknown causes: why up to 5% of cancer patients worldwide In the absence of primary tumors, there are cancer cells spreading. Most importantly, why this early-stage cancer is so difficult to treat. Biologically, this new pattern of early metastasis challenges the cancer we know. How to spread and form everything about metastases, we will have to adjust our thoughts on the topic of tumor metastasis, and we hope that these findings will reshape the way we think about how to treat tumor metastasis."
An important finding of the Mount Sinai research team is that most of the early-proliferating cells remain dormant, and most chemotherapy and targeted therapies target those proliferating cells. Therefore, early spread of cancer cells will evade these conventional treatments, even if they have killed the primary tumor. This work also raises a new question: How do early-staged cancer cells promote tumor metastasis? Is it their own to do this? Did they lay the soil for the tumor cells that were not caught in the early stages of arrival, or did they work with cancer cells that arrived later? This study suggests that a complete understanding of how to target metastatic cancer cells must explore new biological mechanisms of early spread.
2, the University of Regensburg, Germany, published the early dissemination of HER2+ breast cancer
A paper co-authored by Dr. Aguirre-Ghiso, led by Dr. Christoph Klein of the University of Regensburg in Germany, was also published in the journal Nature in the same period.
The Regensburg University team found that cancer cells can spread not only from highly mutated, apparently evolved, and pathologically defined invasive tumors, but also from early cancer cells that are generally considered to be non-proliferative. Team members provided clues about other key mechanisms for how early diffusion was controlled, and in this study demonstrated the preclinical findings of human tumor cells and tumors. The researchers from both teams completed their research independently and then collaborated on the project.
Both groups of researchers studied early stages of breast cancer, including DCIS (mammary ductal carcinoma in situ), DCIS is a non-invasive breast lesion, and 2-3% of women who have received DCIS have died from metastasis. No primary tumor was produced. A key finding of the second paper is that in the mouse model, 80% of metastases originate from early-spreading cancer cells rather than from large tumors. In fact, Klein's team identified a mechanism in which cancer metastasis is more efficient in early lesions than in large tumors.
In both studies, the researchers found that early cancer cell spread is an extension of the normal process of producing ductal branches in females. Two major pathways (the tumor suppressor gene p38 and the oncogene HER2) are activated in this ancient process. Turning off p38 and turning on HER2 activates a node in the EMT (epithelial to interstitial transition) signaling pathway. EMT promotes cell movement during embryogenesis and tissue development. Klein's paper also shows that progesterone receptor signaling, which controls the branching of the mammary tree, is important in early diffusion by regulating the signals involved in EMT and growth processes.
As the mammary gland structure develops, p38, HER2 and EMT alternately open and close, and cooperate with the progesterone signal, allowing the mammary gland cells to move through the mammary gland and hollow the milk duct branch network to the nipple. Dr. Aguirre-Ghiso said that adjusting these pathways is the normal way to form hollow branches.
But in their experiments, they found that if HER2 is over-activated or mutated, and p38 is permanently turned off, EMT is continually activated, allowing cells to move out of the mammary gland through the bloodstream and into the animal.
He said: "We are able to use the three-dimensional culture to build organs, and use high-resolution imaging directly in live animal models to actually observe the blood flow of these cells into the milk duct tree structure and migrate to the lungs, bone marrow and Elsewhere. We have not thought about oncogenes and tumor suppressors before, which is a new function of these pathways.
3. Early spread of breast cancer is similar to other aggressive tumors.
Dr. John S. Condeelis, director of the Gruss Lipper Biophotonics Center, which performs high-resolution in vivo imaging, said, "We were surprised to find that the proliferation mechanism of cancer cells from DCIS-like lesions is similar to that found in invasive tumors, but Showing such a strong ability to spread. This is a new insight that exceeds our expectations."
Although these two studies focus on the mechanisms of early breast cancer transmission, similar processes can control other human cancers, including early spread and metastasis of melanoma and pancreatic cancer. Dr. Aguirre-Ghiso said that in fact, early spread of pancreatic cancer is also associated with the EMT process.
Among the key pathways in their research, Mount Sinai researchers are looking for growth switches that promote early diffusion of dormant cancer cells to form metastases. Dr. Aguirre-Ghiso said: "Although our findings add a new level of sophistication to the understanding of cancer, at the same time, these results add strength to our efforts to stop the metastasis of cancer, ultimately solving the big problem of cancer."
Reference material
Researchers reveal how cancer can spread even before a tumor develops
Early dissemination seeds metastasis in breast cancer
Mechanism of early dissemination and metastasis in Her2+ mammary cancer
Source: Bio-Exploration (micro-signal biodiscover)
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