Why do metastases frequently manifest themselves only following the surgical removal of the primary tumor? An explanation for this occurrence has now been provided by researchers from the Heidelberg University Mannheim Medical Faculty and the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). They were able to pinpoint a cancer cell messenger molecule that locally stimulates the development of the original tumor. The messenger is broken up into two pieces in the circulation, one of which inhibits metastasis. Mice with tumors who were given the metastasis-inhibiting fragment lived with cancer longer than animals who weren’t given treatment.
Doctors who treat cancer are aware of the fact that many of their patients don’t develop the typically fatal metastases until the primary tumor has been surgically removed. Black skin cancer and breast cancer are two conditions where this phenomenon occurs frequently. From this observation, doctors developed the idea of “concomitant tumor resistance.” It says that the primary tumor, which is also called the cancer’s initial focus, has the power to stop metastases, which are the cancer’s daughter tumors, from growing.
The origins of this phenomenon are still not fully understood. According to experts, the immune system and so-called angiogenic factors play a part in how the metastases are connected to the blood vessel system. The daughter tumors require blood supply starting at a size of roughly one millimeter. Scientists were able to show a few years ago that tumors can send out molecules that tell the body to make new blood vessels or proteins that stop new veins from growing, depending on the tissue environment.
The messenger angiopoietin-like 4 has recently received more attention from researchers led by Hellmut Augustin and Moritz Felcht of the German Cancer Research Center and the Mannheim Medical School of Heidelberg University (ANGPLT4). Because there are so many contradictory papers on this topic, we learned about ANGPLT4, according to Augustin. While ANGPLT4 was once thought to encourage the growth of new blood vessels and hence contribute to the development of cancer, other research has been able to demonstrate the exact reverse and demonstrate that ANGPLT4 limits the growth of metastases.
The Heidelberg-Mannheim researchers discovered a startling mechanism after extensive research on human and animal malignancies. ANGPLT4 was discovered to be one of the molecules most highly connected with progressive tumor growth out of 38 different messenger chemicals that affect vascularization and perhaps concurrent tumor resistance.
The original tumor’s cells produce ANGPLT4, which locally encourages the growth of the tumor. The messenger substance is cleaved, nevertheless, if it is discharged into the bloodstream. Both nANGPLT4 and cANGPLT4 are the names of the two cleavage products. The n-fragment (nANGPLT4) is nearly exclusively found in serum for unidentified reasons. The whole molecule and the c fragment of nANGPLT4, on the other hand, bind to a different receptor than nANGPLT4.
By suppressing vessel formation, this receptor flip also prevents macrometastases from spreading. The researchers used a variety of experimental techniques to show this: After being treated with the n-fragment, mice with tumors produced fewer metastases and lived longer.
According to Moritz Fecht, surgical excision of the primary tumor continues to be the best line of action for the majority of malignancies. But as we now know, doing so also dries up the n-fragment’s source, which suppresses metastasis. Individual latent metastatic tumor cells can become active and develop into a harmful macrometastasis if nANGPLT4 is absent, “declaring Moritz Felcht. The authors write: “We can now explain the contradicting results of prior investigations by cleaving the protein in the body and the resultant opposing functions in tumor metastasis,” the authors write.
“Drugs that successfully control metastatic expansion could be of great help to many cancer patients. Some of these medications, nevertheless, have already had unsuccessful clinical trials. However, given the significant benefit such a medication could provide for people who are impacted, it is important to carry out more preclinical and later clinical research on ANGPLT4, “summarizes Hellmut Augustin.
