Researchers show how communication networks within the tumor microenvironment promote cancer growth

Tumors consist of each the actual, malignant cancer cells and healthy, non-transformed cells within the immediate environment. These include, amongst other things, the endogenous scavenger cells of the immune system, called macrophages, in addition to kinds of cells that form connective tissue, equivalent to fibroblasts. Each macrophages and fibroblasts normally contribute to keeping tissue in its original healthy state and to restoring its structure after minor or major damage. These capabilities also play a very important role in defending the body against the proliferation and spread of cancer cells.

Nevertheless, cancer cells have developed strategies to reprogram each macrophages and fibroblasts into tumor-promoting cells. On this process, the fibroblasts are altered in such a way that they modify the tissue structure in order that it helps the tumor cells to survive and spread. For instance, if metastases form within the lung, the fibroblasts within the lung are activated first. Macrophages secrete growth and survival aspects, which the tumors use, for instance, to present themselves a greater supply of nutrients and oxygen.

It has long been assumed in cancer research that the deactivation of specific, non-transformed kinds of cells is perhaps enough for therapy to achieve success. Nevertheless, despite the promising results achieved in research such strategies have up to now hardly been successful within the treatment of patients.

A research team led by Professor Andreas Weigert and Professor Bernhard Brüne from Goethe University Frankfurt has now identified possible reasons for this. For his or her analyses, the researchers used genetically modified mice that spontaneously develop tumors of their breast tissue. Through further genetic modifications, a fat-like molecule produced by the macrophages and released into the tumor environment, the hormone prostaglandin E2, was deactivated within the mammary carcinoma of those mice. Prostaglandin E2 was previously believed – on the idea of cell culture experiments – to have above all tumor-promoting properties. As expected, deactivating prostaglandin E2 also inhibited the expansion of mammary carcinoma within the mice. To the surprise of the research team, nevertheless, tissue analyses showed that the fibroblasts divided extensively and were activated, and at the identical time more metastases developed within the lungs of the mice.

In further trials, the transcriptome of the fibroblasts was analyzed, that’s, all of the genes read from the genome at that time limit. The researchers were in a position to show that prostaglandin E2 keeps the fibroblasts in mammary carcinoma in an inactive state by way of a previously unknown signaling pathway, which explains why removing the molecule within the mice led to increased metastasis. The method is evidently similar in humans: Fibroblasts activated in an identical way were also present in the breast tumors of some patients, and these patients were far less more likely to survive.

In the middle of their histological study of mammary carcinoma, the researchers also encountered a subgroup of macrophages which, just like fibroblasts, produce parts of the extracellular matrix (the connective tissue between the cells) – above all collagens. Such macrophages, called fibrocytes, were already known from fibrotic disorders (pathological proliferation of connective tissue) of the lung, but their role in tumors was unclear.

That’s the reason the researchers in Frankfurt, along with Professor Rajkumar Savai from the Max Planck Institute for Heart and Lung Research in Bad Nauheim, examined the role of fibrocytes in lung tumors by systematically deactivating them during tumor growth. Via single-cell sequencing, they were in a position to corroborate, amongst other things, that these cells are a key population which coordinates each the expansion of the tumor cells and their supply with blood vessels in addition to the tumor-promoting activation of other macrophage subtypes.

“The outcomes of our studies illustrate that there are lots of kinds of cells within the tumor microenvironment that promote tumor survival, growth and spread in an identical way. The tumor uses central molecular hubs through which it concurrently reprograms various endogenous cells into tumor promoters. If we would like to fight cancer effectively, we want to advance the detection and therapeutic use of such hubs,” says Weigert, summarizing the study results, which were published within the renowned journals Cancer Research and Nature Communications. Identifying such hubs might be a research priority for the participating laboratories in the longer term.