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Internal Mechanism Found Responsible for Limitless Growth Potential of Epithelial Tumors

Researchers from the Development and Growth Control Laboratory at IRB Barcelona have identified the cell types and molecular mechanism responsible for the unlimited growth potential of epithelial tumors (carcinomas) and demonstrated that the growth of these tumors is independent of the tumor’s microenvironment. "In epithelial tumors caused by chromosomal instability or loss of cell polarity, the interaction between two tumor cell populations drives malignant growth," explains Dr. Marco Milán, ICREA Research Professor and Head of the laboratory. Published as the cover story of the August 29, 2017 issue of PNAS, the study analyzes solid tumors of epithelial origin in the fruit fly Drosophila melanogaster. "We have induced tumor development in two ways--by generating genomic instability and the loss of cell polarity. We have validated the causal relation between these two conditions--which are frequently observed in carcinomas--and the development of tumors," explains Dr. Mariana Muzzopappa, first author of the study and postdoctoral fellow in the Development and Growth Control Lab. The PNAS article is titled “Feedback Amplification Loop Drives Malignant Growth in Epithelial Tissues.” To study the effect of the microenvironment on tumor development, the researchers examined tumor growth in the absence of adjacent cell populations, such as cells of the immune system or mesenchymal cells, which can act as a niche by supplying tumors with growth factors. The scientists observed that the tumor continued to grow in the absence of these two cell types. Furthermore, they demonstrated that "the growth of epithelial tumors is dependent on activation of the JNK stress signaling pathway and that this pathway is intrinsically activated in the tumor, regardless of its microenvironment," highlights Dr. Milán. The researchers have identified two functionally distinct cell populations within the tumor--one that proliferates and ones that does not--upon which internal growth mechanisms depend.

"JNK is activated in a group of non-proliferating cells, namely those that show the highest degree of chromosomal instability or that have lost polarity. JNK triggers the expression of growth factors and makes those cells still in the epithelium to go on proliferating. The continued proliferation of these cells leads to an increase in chromosomal instability and the loss of epithelial polarity in the tumors. Consequently, the number of cells expressing growth factors rises. These cross-feeding interactions explain the unlimited growth potential of these epithelial tumors," says Dr. Muzzopappa.

The mechanism of JNK activation differs depending on the tumor. "We have observed that tumors derived from chromosomal instability are induced by oxidative stress caused by ROS (reactive oxygen species), which triggers JNK. The mechanism in tumors that arise from the loss of cell polarity differs," explains Dr. Milán.
The results of this study shed further light on the causal relationship between chromosomal instability, loss of epithelial polarity, and tumorigenesis and open new avenues for the search of therapeutic targets.

A third author on the paper is PhD student Lada Murca.

IMAGE

Image shows tumor (red) covered by collagen (green), which is being deposited by cells of the immune system (cyan). (Credit: Mariana Muzzopappa, IRB Barcelona).

[Press release] [PNAS abstract]