Why does cancer metastasis usually appear only after surgery to remove the tumor?

Why do metastases usually appear only after surgery to remove the tumor? Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Mannheim Medical School of the University of Heidelberg have now published an explanation
for this phenomenon.
They were able to identify messenger substances in cancer cells that locally promote the growth
of the primary tumor.
In the blood, the messenger is split into two fragments, one of which inhibits metastasis
.
Tumor-bearing mice treated with metastasis-inhibiting fragments survived longer
than mice that did not receive treatment.

Cancer doctors are familiar with the observations: In many of their patients, often life-threatening metastases appear
only after the primary tumor has been surgically removed.
This phenomenon is especially common
in breast and dark skin cancers.
From this observation, doctors deduced the concept of
"accompanying tumor drug resistance".
It states that the initial tumor lesion, also known as the primary tumor, can inhibit the growth
of daughter tumors (metastases).

The reasons for this phenomenon are still poorly
understood.
Experts believe that the immune system works together with so-called angiogenic factors, which affect the connection of
metastases to the vascular system.
Starting at about a millimeter in size, daughter tumors rely on a vascular supply
.
Researchers were able to show years ago that, depending on the tissue environment, tumors either release messengers that promote the formation of new blood vessels or factors
that inhibit the growth of new veins.

Scientists led by Hellmut Augustin and Moritz Felcht of the German Cancer Research Center and the Mannheim Medical School of the University of Heidelberg are now taking a closer look
at messenger-like angiopoietin-4 (ANGPLT4).
"We started to notice ANGPLT4 because there are many conflicting publications
on this factor," Augustine said.
"While ANGPLT4 was originally described as promoting the formation of new blood vessels and thus cancer, other studies have been able to demonstrate the exact opposite, showing that ANGPLT4 inhibits the development of
metastasis.
"

In a series of comprehensive experiments on human and mouse tumors, the Heidelberg-Mannheim team elucidated a surprising mechanism
.
Among 38 different messenger substances acting on vascularization and possible tumor resistance, ANGPLT4 was found to be one of the molecules most closely related to tumor progression and growth

ANGPLT4 is produced by primary tumor cells and locally promotes tumor growth
.
However, if the messenger substance is released into the bloodstream, it is cleaved
.
These two lysis products are called nANGPLT4 and cANGPLT4
.
For reasons that are not fully understood, n-fragments (nANGPLT4) are found almost exclusively in
serum.
However, nANGPLT4 binds
to a different receptor than the intact molecule or c-fragment.

This receptor switch inhibits the growth of blood vessels, which inhibits the growth
of large metastases.
The researchers demonstrated this in a number of experimental methods: after treatment with n-fragments, tumors that metastasized to mice formed less metastases and the animals survived longer
.

"Of course, surgical removal of the primary tumor is still the gold standard for most cancer treatments," says
Moritz Fecht.
"But we now understand that this also dries up
the source of n-fragments that inhibit metastasis.
" If nANGPLT4 is lost, a single dormant metastases cells become active and develop into dangerously large metastases," says
Moritz Felcht.
"By cleaving proteins in vivo and the resulting opposite functions in tumor metastasis, we can now explain conflicting results
from previous studies.
"

"Many cancer patients can benefit from
drugs that effectively inhibit metastatic growth.
However, some of these drugs have failed in clinical trials
.
But given the potential for huge benefits of this drug for those affected, it is worthwhile to continue to study the preclinical and clinical aspects of ANGPLT4," concludes Hellmut Augustin
.

Journal Reference:

1. Corinne Hü bers, Ashik Ahmed Abdul Pari, Denise Grieshober, Martin Petkov, Alexander Schmidt, Tatjana Messmer, Christian Moritz Heyer, Sebastian Schö lch, Stephanie S.
   Kapel, Nicolas Gengenbacher, Mahak Singhal, Benjamin Schieb, Claudine Fricke, Rainer Will, Kim Remans, Jochen Sven Utikal, Christoph Reissfelder, Matthias Schlesner, Kairbaan M.
   Hodivala-Dilke, Sander Kersten, Sergij Goerdt, Hellmut G.
   Augustin, Moritz Felcht.
   Primary tumor– derived systemic nANGPTL4 inhibits metastasis.
   Journal of Experimental Medicine, 2023; 220 (1) DOI: 10.
   1084/jem.
   20202595