Reprogrammed macrophages promote spread of breast cancer

Date:
April 25, 2022
Source:
German Cancer Research Center (Deutsches Krebsforschungszentrum,
DKFZ)
Summary:
Metastatic breast cancer cells abuse macrophages, a type of
immune cell, to promote the settlement of cancer metastases in the
lungs. The reprogrammed macrophages stimulate blood vessel cells
to secrete a cocktail of metastasis-promoting proteins that are
part of the so-called metastatic niche.



FULL STORY ========================================================================== Metastatic breast cancer cells abuse macrophages, a type of immune
cell, to promote the settlement of cancer metastases in the lungs. The reprogrammed macrophages stimulate blood vessel cells to secrete
a cocktail of metastasis- promoting proteins that are part of the
so-called metastatic niche. This was demonstrated by scientists from
the German Cancer Research Center and the Stem Cell Institute HI-STEM*
in mice that had been transplanted with human breast cancer cells. The
work enabled the scientists to identify new targets and develop initial concepts to better restrain the metastatic spread of breast cancer.


========================================================================== Cancer spreads within the body as individual cells detach from the
primary tumor and travel to distant body regions via the bloodstream or lymphatic system. Before they can grow into a metastasis at a secondary
site, they must communicate with their new environment through a variety
of molecular interactions. "In order to settle in this new, hostile
milieu, the cancer cells corrupt the microenvironment to support their
growth," says Thordur Oskarsson of the German Cancer Research Center
(DKFZ) and the stem cell institute HI- STEM. Researchers refer to this
as the tumor cells creating a "metastatic niche." Blood vessels play
a very special role in metastasis. Detached tumor cells prefer to stay
in their immediate vicinity. In particular, the interactions of cancer
cells with the endothelial cells lining the inside of the vessels are
crucial for metastasis, as many studies have already shown. However,
the details of this molecular exchange are still largely unknown.

A team led by Oskarsson has now investigated these interactions during metastatic colonization of the lung by breast cancer cells in mice. The researchers first observed that four genes in the lung endothelial
cells showed a particularly strong increase in activity three weeks
after the onset of metastasis. They encode four proteins that are
secreted into the microenvironment (Inhbb, Lama1, Scgb3a1 and Opg**),
which both individually and in combination promote the development
of lung metastases. Inhbb and Scgb3a1 confer stem cell properties to
cancer cells, Opg prevents programmed cell death -- apoptosis -- and
Lama1 supports adhesion-mediated cell survival.

Importantly, high expression of these four newly identified niche factors correlates with both shortened relapse-free survival and shortened
overall survival of breast cancer patients.

But how do cancer cells get the lung endothelium to produce the
metastasis- promoting protein cocktail? To the surprise of the scientists,
the cancer cells do not do this job directly themselves, but instead
harness a cell type of the innate immune system for this purpose,
the macrophages.

"These macrophages, which often reside in the vicinity of the lung blood vessels, are activated by tenascin, an extracellular matrix protein
produced by breast cancer cells," explains Tsunaki Hongu, the first
author of the study.

Tenascin is involved in disease progression in many cancers. After
activation by tenascin, macrophages produce various factors that induce
the production of the cancer-promoting protein cocktail in endothelial
cells. By eliminating macrophages or their activity, using specific
molecular agents, the investigators could show that these cells are
crucial for production of the metastasis-promoting protein cocktail.



========================================================================== Oskarsson, who now works at H. Lee Moffitt Cancer Center and Research
Institute in Tampa, Florida, summarizes: "The complexity of the crosstalk between cancer cells, macrophages and endothelial cells is striking. With
a better understanding of the numerous proteins and other factors
involved in these metastatic interactions, we were able to identify
a variety of starting points for new strategies against breast cancer metastasis. We have already developed initial therapeutic concepts for
this, which we now need to validate in further studies." Notes * The Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) gGmbH was founded in 2008 as a public-private partnership by
the DKFZ and the Dietmar Hopp Foundation.

** Inhbb: Inhibin Beta B Lama1: Laminin Subunit Alpha 1 Scgb3a1:
Secretoglobin 3A1 Opg: Osteoprotegerin

========================================================================== Story Source: Materials provided by
German_Cancer_Research_Center_(Deutsches
Krebsforschungszentrum,_DKFZ). Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Hongu, T., Pein, M., Insua-Rodri'guez, J. et al. Perivascular
tenascin C
triggers sequential activation of macrophages and endothelial
cells to generate a pro-metastatic vascular niche in the lungs. Nat
Cancer, 2022 DOI: 10.1038/s43018-022-00353-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220425121056.htm

--- up 8 weeks, 10 hours, 51 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)