The world outside the cell
The cellular micro-environment.
The human body has been shown to have 37.2 trillion cells (1), all doing their own business in the respective tissues where they belong. But remember, each of those 37.2 trillion cells originated from that first cell which came into being, when the egg met the sperm! How then did that one cell multiply to make so many different types of cells? How does the cell on your toe behave so differently from the cell in your eye, even tough they all have absolutely the same genetic material? Yes, you can attribute this to the difference in the epigenetic and transcriptional profile of the cells, but another aspect that doesn’t receive much attention, but needs to be factored in here, is the cellular microenvironment.
The cell is not a stand-alone entity. Its functioning is largely dependent on its microenvironment, which comprises of a complex milieu of structural proteins, proteoglycans and enzymes (collectively called the extracellular matrix or ECM) and a variety of cells such as – fibroblasts, immune cells and endothelial cells, keeping the cells in place and sending signals that allow them to carry out their routine function.
Mina Bissel and co-workers in the year 1989 conducted a very interesting experiment (2) to show this using breast epithelial cells. Before going into that, lets briefly look into the mammary gland. The mammalian mammary tissue at puberty consists of a fat pad with a branching unit made of ducts and lobules. This branching entity is lined with epithelial cells, with their basal surface, firmly tethered to a fibrous, collagen rich entity of the ECM called basement membrane and their apical surface facing the lumen (central opening), i.e. they have polarity.
During pregnancy, under the influence of progesterone and prolactin, these units become highly branched, undergoing alveologenesis and secrete milk into the lumen (3). In order to study these mammary epithelial cells, scientists routinely grow these cells (extracted from patient biopsies or cultured cell lines) on plastic petri dishes, where these cells spread on a 2D plane. However, they show no glandular architecture, no polarity and in no way represent the actual 3D conformation they exist in, in the body.
What Mina Bissel and co-workers did, is that they grew these mammary epithelial cells on a re-constituted basement matrix which mimics the basement membrane, comprising proteins such as collagen and laminin. What they observed was incredible! They observed that the same cells were now capable of forming a 3D spherical, alveolar architecture, with cells showing polarity, i.e. the basal side anchored to the basement membrane and the apical side facing the lumen. Not just that, using immunoprecipitation experiments they showed that, under the influence of lactogenic hormones, 80% of caseins (milk protein) was secreted into the lumen. The cells were making milk!
What we see from this, is the importance of the cellular microenvironment, more significantly the protein rich ECM in the functioning of the cell. Cells, that little idea of what they had to do when grown on plastic, regained much of their functionality when grown on a protein rich ECM.
The role of the ECM can be fully appreciated in the context of tissue homeostasis. Cells are constantly exposed to various kinds of stress and that would mean that at this given moment, your body may easily have numerous tumorigenic cells. But these cells are constantly kept in check by its microenvironment and they will have to overcome these antitumorigenic pressures to establish a full blown tumour.
The cellular microenvironment indeed acts as a guardian (4). But very often in cancerous tissues, it is observed that these very guardians can behave as partners in crime and facilitate the cancer cells to metastasise. Researchers are now trying to understand the signalling mechanisms that facilitate this partnership. Understanding this will not only give us better insight into the pathogenesis of cancer but will also help us to understand in general how tissue architecture and homeostasis is elegantly maintained in the body.