The expansionism of cancer cells
Scientists have made the startling discovery that cancer cells have the capacity to ‘corrupt’ their healthy neighbours into aiding and abetting their metastatic crusade.1 Sort of like that bad egg who convinces their straight- laced friends that doing drugs is a good idea. As part of a larger study to investigate the tumour microenvironment (TME), Dr. Ilaria Malanchi’s group at the Francis Crick institute in London, in collaboration with other research groups across Europe identified a population of cells that bear resemblance to stem cells and are able to support cancer development. This is exciting because this insight into the TME allows scientists to identify new drug targets and study how cancer cells are able to rapidly proliferate.
The tumour microenvironment
Let me take a step back. What is this tumour microenvironment I speak of? To put it simply, it is the environment surrounding a tumour. It includes blood vessels, various cell types including fibroblasts and inflammatory cells, signalling molecules and the extracellular matrix.2 It has been known for a while now that cancer cells and the TME share a symbiotic relationship. However, not much is known about how metastatic cells cause early cellular changes within the TME. To answer this question, scientists designed an ingenious system wherein the metastatic cancer cells were engineered to secrete a fluorescent protein that could be taken up by neighbouring cells. This allowed them to spatially study the immediate microenvironment of those metastatic cells.
The fluorescent protein labelling system
Fluorescent labels are amazing. Potentially, any protein in a cell can be tagged with a fluorophore and easily tracked using a confocal microscope. Also, the pictures are usually so colourful and pretty!3 In this study, a modified peptide (very small protein) called sLP was tagged with mCherry (yes it gives out a lovely red colour when excited with a laser (540- 590 nm)). Mouse origin breast cancer cells called 4T1, that are typically used to study metastasis, were engineered to co- express sLP- mCherry and GFP. Why GFP? As the 4T1 cells would be the only ones expressing GFP, researchers could distinguish them from other neighbouring cells. When these engineered 4T1 cells were injected intravenously into mice to induce a lung metastasis, researchers found that sLP- mCherry could label surrounding host tissue cells. It could do that as it is a naturally secreted protein that is soluble in lipids. This means that once its secreted from a cell, it can cross the cell membrane of a neighbouring cell. This specific labelling allowed researchers to differentiate lung tissue immediately affected by the metastatic cells from more distal lung tissue. Using this strategy, the scientists could study all the various cell types that make up the TME around metastatic cells. It was during this process that they identified lung epithelial cells that expressed markers normally present in progenitor cells (cells that differentiate into other cell types). Through in vitro studies, they were able to establish that this modification in the epithelial cells was a direct result of the breast cancer cell metastasis to the lung.
Why should people care about this research?
The science sounds really cool, but other than that, why should people care? Why is this research important? I should emphasise at this point that the opinions here are my own. Firstly, the discovery that breast cancer metastasis to the lung leads to a stem- cell like regenerative phenotype in epithelial cells gives scientists a new target for therapy. Studying these cell populations in the TME can allow for the development of novel drugs that could potentially target these cells and halt or at least slow down cancer metastasis. The fluorescent protein technology used in this paper can also be used to interrogate the TME and metastasis of other cancers. It can also potentially be applied to other fields such as stem cell biology and developmental biology to track cellular differentiation.4 This opens up so many new avenues for research and development. In conclusion, the bottom line is that cancer cells are not great in general, but it turns out that they can be a really bad influence on their healthy neighbours.
1. Ombrato, L. et al. Metastatic-niche labelling reveals parenchymal cells with stem features. Nature 572, 603–608 (2019).
2. Wang, M. et al. Role of tumor microenvironment in tumorigenesis. J. Cancer 8, 761–773 (2017).
3. Toseland, C. P. Fluorescent labeling and modification of proteins. J. Chem. Biol. 6, 85–95 (2013).
4. Islam, I. et al. In Vitro Osteogenic Potential of Green Fluorescent Protein Labelled Human Embryonic Stem Cell-Derived Osteoprogenitors. Stem Cells Int. 2016, (2016).