New breakthrough: This collagen can make tumor cells dormant!
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New breakthrough: This collagen can make tumor cells dormant!
Tumor metastasis is the main cause of death of cancer patients, and it is also an important challenge faced by oncologists.
After the primary tumor is removed, if adjuvant therapy cannot completely remove the remaining tumor cells, these tumor cells will reach distant organs through blood circulation, colonize, and enter a dormant state. After a few years, dormant tumor cells are activated by specific conditions. Proliferate rapidly and form obvious metastases.
Once the tumor cells enter dormancy, the cell cycle stagnates in the G0/G1 phase, and the cells do not proliferate or apoptosis, traditional radiotherapy and chemotherapy will lose their effect, making it more difficult to completely cure the tumor.
Therefore, some scholars have proposed that it can be activated The dormant tumor cells are swept away.
The problem is that the gene expression of dormant tumor cells and primary tumor cells are no longer the same.
The original treatment plan does not necessarily affect the activated cells. If you rashly activate dormant tumor cells, you may usher bad results.
Therefore, another group of scientists decided to do the opposite, either to let this batch of dormant tumor cells dormant permanently to prevent them from waking up, or even more ruthlessly, to destroy them directly while they are dormant, perhaps to avoid tumor recurrence. .
To make tumor cells dormant, it is necessary to understand the mechanism of their dormancy.
A research team from the Icahn School of Medicine at Mount Sinai in the United States recently published a study in Nature Cancer, which revealed that the extracellular matrix in the tumor microenvironment has an effect on tumor cell entry and The key role of maintaining the dormant state.
Researchers first started with the nest of dormant tumor cells to explore what is so special about this tumor microenvironment that can make tumor cells sleep here?
Dormant tumor cell lines and proliferative tumor cell lines are inoculated into mice by tail vein injection.
Unlike proliferative tumor cells that rapidly form tumors in mice, dormant tumor cells are usually single in mice. Exist in the form of cells or inert nodules.
Under multiphoton second harmonic imaging, the researchers observed:
The extracellular matrix of dormant tumors is mainly composed of curled, disorderly collagen fibers, while the extracellular matrix of proliferating tumors is a straight, more directional linear arrangement.
Legend: Domant dormant type; Proliferative proliferative type
As the tumor progresses, the arrangement of collagen fibers in the extracellular matrix of the tumor is also undergoing dynamic changes.
The more advanced the tumor develops, the curled collagen fibers become more and more orderly.
What’s even more amazing is that when researchers inoculated mice with proliferative tumor cells, they were surgically removed to simulate clinical tumor surgery patients.
There are a small amount of residual tumor cells on the edge of the surgical wound.
When these residual tumor cells recur in situ or distant metastasis and relapse from a dormant state to a proliferation state, the collagen fibers around the cells have also undergone changes from curling to straight.
Legend: Left: Tumor recurrence in situ, Right: Tumor lung metastasis and recurrence
These results together indicate that the extracellular matrix structure is closely related to the dormant-resuscitation state of tumor cells-the collagen around the dormant tumor cells is curled up and distributed.
Once the dormant cells are resuscitated and proliferate, the surrounding collagen presents a linear distribution.
Furthermore, the researchers performed mass spectrometry analysis on decellularized tumor masses to study the difference in the composition of tumor cell extracellular matrix components in dormant and proliferating states, and found that compared with proliferating tumor cells, the type III collagen in dormant tumor extracellular matrix The content is significantly increased.
Transcriptomics analysis of tumor cells can also see that the expression of COL3A1 in dormant tumor cells has increased.
Legend: Type III collagen (red fluorescence), T-HEp3 proliferative head and neck squamous cell carcinoma cell line, D-HEp3 dormant head and neck squamous cell carcinoma cell line
At the same time, the clinical biopsy of the primary tumor site in patients with head and neck squamous cell carcinoma showed that those patients with lymphatic metastasis had a higher level of type III collagen than those without metastasis. Low.
Legend: N0 tumor patients without lymphatic metastasis, N+ tumor patients with lymphatic metastasis
The above results indicate that the higher the content of type III collagen in the tumor microenvironment, the more prone to dormancy of tumor cells.
The lower the content of type III collagen, the more active the tumor cells are and the easier it is to metastasize.
In the next step, in order to prove whether type III collagen is the key for tumor cells to “stroke from the cliff” into a dormant state, the researchers combined the proliferative tumor cells with type I collagen, type III collagen, type IV collagen, and Dulbecco’s phosphate buffer.
The solution (DPBS) was inoculated to chicken chorioallantoic membrane, and it was found that:
The tumor cells injected with type III collagen formed smaller tumor masses, and the phosphorylation level of histone H3 related to tumor cell proliferation was down-regulated, while the expression of the dormant marker nuclear protein p27 increased, indicating that type III collagen inhibited tumor cells Proliferate and induce tumor cells to enter a dormant state.
Next, in order to verify whether type III collagen can inhibit the proliferation of residual tumor cells at the primary tumor resection site, the researchers covered the tumor resection site with a dental sponge infiltrated with type III collagen, and the control group covered the corresponding site with infiltration DPBS The sponge, tracking the local tumor recurrence of the two groups of mice, found that:
Only 20% of the mice implanted with the type III collagen bio-scaffold had tumor recurrence, while the control group mice had a tumor recurrence probability of 80%!
Legend: Blue: Type III collagen group Orange: Local recurrence of tumors in the DPBS group
More importantly, type III collagen not only inhibits tumor proliferation and induces tumor cells to enter a dormant state, but is also the key to tumor cells to maintain a dormant state.
After the COL3A1 gene of dormant tumor cells is knocked out, dormant tumor cells are no longer dormant and proliferate and grow rapidly after planting.
If proliferative tumor cells overexpress COL3A1, cell proliferation will be inhibited, and tumor masses formed after planting will be smaller. , Once again proved that type III collagen is indispensable in the process of tumor cell dormancy.
Finally, in order to ascertain the signal pathways through which type III collagen induces and maintain tumor cell dormancy, after a series of gene knockout and salvage experiments, the researchers found that there is a gap between type III collagen and dormant tumor cells. Positive feedback path:
The type III collagen that promotes dormancy binds to tumor cell DDR1 receptors, activates STAT1 to enter the nucleus, promotes the expression of COL3A1, tumor cells secrete type III collagen, and tumor cells maintain dormancy.
All in all, this study reveals the influence of tumor microenvironment on tumor cell dormancy, and proves that type III collagen plays an important role in it.
Adding type III collagen to the tumor microenvironment can promote tumor cells to enter and maintain a dormant state. , Inhibit tumor proliferation.
Keeping the remaining tumor cells in tumor patients in a dormant state can prevent tumor recurrence and prolong patient survival.
Clinical trials using “5-AZA+ all-trans retinoic acid” to inhibit the recovery of dormant tumor cells in prostate cancer patients have been launched ( NCT03572387).
In the future, type III collagen may be used as a marker for predicting tumor recurrence and a treatment to maintain tumor cell dormancy and prevent tumor recurrence.
(Ps: Type III collagen can only play a role in promoting dormancy in the tumor microenvironment. No one thinks that oral type III collagen can fight cancer, right?)
references:
[1] Di Martino, J.S., Nobre, A.R., Mondal, C. et al. A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy. Nat Cancer (2021).
[2] Sosa MS, Bragado P, Aguirre-Ghiso JA. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer. 2014;14(9):611-622.
[3] Aguirre-Ghiso, J., Bragado, P. & Sosa, M. Metastasis Awakening: Targeting dormant cancer. Nat Med 19, 276–277 (2013).
New breakthrough: This collagen can make tumor cells dormant!
(source:internet, reference only)
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