It may seem odd to the point of negligence that a problem mankind has been grappling with since at least the time of the ancient Egyptians should, within the last ten years or so, be shown to have a whole new dimension, scarcely conceived hitherto. This hidden world, often now called the tumour microenvironment, is created as solid tumours develop and attract a variety of normal cells from the host to form a cellular cloud that envelops them and supports their growth (as we noted in Cooperative Cancer Groupies). We shouldn’t beat ourselves up for being slow to grasp its existence yet alone its importance – just take it as a reminder of the multi-faceted complexity that is cancer.
It’s true that over one hundred years ago the London physician Stephen Paget came up with his “seed and soil” idea – the notion that when cells escape from a primary tumour and spread to secondary sites (metastasis) they need to find a suitable spot that will nourish their growth, otherwise they perish – a fate that befalls most of them, fortunately for us.
But in the twenty-first century …
Perceptive though that idea was, it didn’t relate to the goings on in the vicinity of primary tumours – where the current picture is indeed of a cosmopolitan crowd of cellular groupies being recruited as the tumor starts to grow such that they infiltrate and closely interact with the cancer cells. The groupies are attracted by chemical messengers released by tumour cells – but it becomes a two-way communication, with messenger proteins shuttling to and fro between the different cell types.
Two-way communication between host cells and tumor cells.
White blood cells (e.g., lymphocytes and macrophages) are one group that succumbs to the magnetism of tumours. They’re part of the immune response that initially tries to eliminate the abnormal growth but, in an extraordinary transformation, when tumour cells manage to evade this defense the recruited cells change sides so to speak, switching their action to release signals that actively support tumor growth. The idea of boosting the initial anti-tumour response, thereby using the host defence system to increase the efficiency of tumour elimination, is the basis of immunotherapy, a popular research field at present to which we will return in a later piece.
Who’s who among the groupies
The finding that cells flooding into the ambience of a tumour can affect growth of the cancer has focussed attention on identifying all the constituents of the cellular cloud and unraveling their actions. Two recent studies by Claudio Isella from the University of Turin and Alexandre Calon from Barcelona, with their colleagues, have looked at a type of bowel cancer that has a particularly poor prognosis and used an ingenious ploy to lift the veil on who’s doing what to whom in the tumour milieu.
The tumours were initially classified on the basis of a genetic signature – that is, a snapshot of which genes are active in a tumour sample – ‘switched on’ or ‘expressed’ in the jargon – meaning that the information encoded in a stretch of DNA sequence is being used to make a functional gene product, usually a protein. They then used the crafty tactic of implanting human tumour cells into mice (the mice are ‘immunocompromised’ so that they don’t reject the human cells), separated the major types of cell in the tumours that grew and then looked at the genes expressed in those sub-sets. Remarkably, it emerged that, of the cell groupies that infiltrate into primary tumours, fibroblasts are particularly potent at driving tumour growth and metastasis. Fibroblasts are a cell type that makes the molecular scaffold that gives structure and shape to the various tissues and organs in animals – so it’s a surprise, to say the least, to find that cells with a rather mundane day job can play an important role in cancer progression. In this model system the sequence differences between corresponding human and mouse genes confirm that the predominant driver is mouse cells infiltrating the human tumours. Perhaps it shouldn’t be quite such a shock to find fibroblasts dabbling in cancer as we have met cancer-associated fibroblasts (CAFs) before as cells that, by releasing leptin, can promote the growth and invasion of breast cancer cells (in Isn’t Science Wonderful? Obesity Talks to Cancer).
How useful might this be?
As ever, this is just one more small step. However, the other key finding from this work is that a critical signal for the CAFs is a protein called transforming growth factor beta (TGFβ) and a small molecule that blocks its signal inhibits metastasis of human tumour cells in the mouse model. So yet again the cancer biologist’s best friend gives a glimmering of hope for human therapy.
Isella, C. et al. (2015). Stromal contribution to the colorectal cancer transcriptome. Nature Genet. http://dx.doi.org/10.1038/ng.3224
Calon, A. et al. (2015). Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nature Genet. http://dx.doi.org/10.1038/ng.3225