Mucus is very difficult to clean off and it is usually a tough job trying to maintain hygiene when suffering from a flu. This should not make you fret, as its stickiness is a key in-built feature that mediates its functions. Bacteria, viruses, and dust find it equally as hard as us to escape from mucus. They become entrapped in mucus not just because it acts as a physical barrier made up of intercrossing fibers forming a steric sieve, but also it incorporates a broad range of entrapping mechanisms everything from electrostatic and hydrophobic lodgment all the way to hydrodynamic and mechanical hindrance making it almost impossible for anything to escape from it.
Now that we can see eye to eye about the “sticky icky” nature of mucus, I will discuss how mucus barriers stand between us and the successful future treatment of cancers. Adenocarcinomas that may form in the colon, stomach, breast, pancreas, ovaries, lung or prostate are a type of resistant malignancies that comprise of a population of cancer cells enveloped by a thick layer of mucus. This mucus mesh hinders the diffusion and homogeneous distribution of drug laden nanoparticles throughout a tumor, preventing their functional accessibility to cell membranes and subsequent uptake by cancer cells. It is not just the up-regulated expression of mucus that can obstruct the flux of nanoparticles that concerns us, but also the thicker consistency that mucus manifests in cancer. In fact, there were several reports to date suggesting the fortification of mucous barriers in cancer i.e. mucus in cancer is several fold tougher than normal mucus.
Mucins (mucus glycoproteins) in humans fall under two dichotomies a) gel-forming and b) membrane-tethered, with the latter having an ectodomain protruding several hundred nanometers from the surface of a cell. Inasmuch as healthy cells recruit mucus for survival and prevalence over toxins and other insults, cancer cells uses mucus to wield control over their microenvironment and establish a favorable milieu for their growth. There is building evidence supporting the fact that mucus is not only a static physical barrier that protects cancer cells. It is also an active and dynamic domain that orchestrates cell-cell and cell-ECM interactions leading to the immune surveillance evasion, progression and metastasis of cancer.
Instead of going on board with strategies like the administration of systemic mucolytics or mucus biosynthesis enzyme inhibitors as adjuvant therapy in cancer, which safety and associated side-effects are still a matter of debate. In my PhD project, we decided not to devise tactics to deconstruct the mucus and we made no effort whatsoever to alter its barrier properties. Instead, we were set to delineate the nanostructure of mucus to obtain a better understanding of what can and cannot cross the mucus. Atomic force microscope will be put to use to unveil several properties of mucus with great finesse and detail. Barrier properties of mucus will be contextualized to identify the design rules of NP (i.e. size, charge, coating etc.) that would yield the greatest cellular uptake and most homogeneous distribution in tumors.
Results and technologies developed from this project can be seamlessly integrated within treatment protocols of adenocarcinoma of different origins and will have a resounding clinical impact on the disease prognosis for many cancer patients who are refractory to current treatment plans and have dismal survival rates.
PhD student, Pathchooser fellow
EPOS-IASIS Research and Development Ltd