Are CANCER & BLINDNESS Linked?

How the Matrix influences BOTH Glioma and Retinitis Pigmentosa

Retinitis Pigmentosa (RP) is a form of blindness that is often called tunnel vision. With RP one’s peripheral vision is lost leaving just the center of the image. In some ways the opposite to macula degeneration where the core of the image is lost but the edges are intact. The pathology results from pigmented cells at the back of the retina invading and killing off the retinal cells that are our sensors for light (rods and cones). This invasion occurs at the periphery and works its way to the center as vision is slowly compromised.

So how is this related to cancer? Let’s start with how cells know where they are, and how in cancer they lose control of their growth & spread (metastases).

On the surface RP is clearly not the same as cancer. RP may be debilitating but it is not a fatal disease. The pathology reflects too many pigmented cells in the wrong place. However, if you think about it, there are similar elements to how solid tumors, like brain cancer, spread in an excessive and uncontrolled manner. For many decades, cancer researchers thought that the critical “cancer event” was a mutation where the cells either have lost the influence of a tumor suppressor gene, or they activated an oncogene ie a growth promoting gene. In other words, the focus was on a disturbed genetic compromised.

Influence of the Matrix

In many cases this genetic focus holds true, but there are also plenty of exceptions. By studying where the premise fails that where we can truly learn the nuances of the disease.

Biomedical research is all about looking for commonalities and learning from exceptions.

Another mechanism that has growing attention as a potential explanation for some cancer lies outside the cancer cells themselves. Cancer researchers are now investigating extracellular structure which the cells are held together and connected — The MATRIX. For many years we though the matrix was inert, like a scaffolding, but not really the main show in town. Now we know cells behavior and function is intimately dictated by this scaffolding. The matrix can influence the activity, the tone, the actions and desires of the cells that are connected to them. On occasion, this interaction may go array, and as a result they cells are driven to replicate and spread in an uncontrolled manner.

Disturbances in the matrix may or may not be the core problem, but they can be the trigger that literally opens the door and lays down the carpet for tumor growth and metastasis

When cancer researchers look outside the cell they find an enormous array of proteins, glycoproteins (proteins with sugar residues attached to them) and polysaccharides that form the MATRIX. In an analogous manner snails and other gastropods lay down a strip of mucus (polysaccharides) to allow them to move forward in the direction they desire. For cancer this is done at a cellular level. Note that snail mucus is essentially in the same as molecular family known as hyaluronic acid, which is a lubricant for joints and a matrix element is mammalian skin and tissues.

When there is an alteration in the nature of this matrix, either by volume, relative structure, mutational alterations, degrading proteases, inflammation or through damage, then the cells may change their behavior, actions and intent. Invariably this will involve contributions by the cells that lay down the matrix e.g. the fibroblasts or reticulo-endothelial cells.

For some cancers the core problem may resides outside the “cancer cells” and in the matrix upon which they reside which gives the cells misleading directions like a deranged GPS.

So what is the evidence for this concept?

Let’s address the premise with a focus on a single matrix element, a glycoprotein called Tenascin-C (TNC). The structure of tenascin-C is interesting in that it arises from a multi-modular assembly that easily establishes a number of variants. Originally associated tendons (hence the name), there are actually 4 tenascins. Tenascin-C is a large, multimodular, extracellular matrix glycoprotein that facilitates tissue growth and maturation in the embryo, but levels drop off dramatically in adults ( Tenascin C form and Function ). Where TNC is found in adults is in tissue that is undergoing turnover, remodeling or wound healing e.g., stem cells, the nervous system, ligaments, tendons and muscles.

Tenascin-C as it is being assembled can interact with at least 25 different other molecules to affect cell behavior and decision making. There are also 26 different potential sites for glycosylation (addition of sugar residues) that can substantially affect form and function. Focusing on cancer, variances in the structure of TNC as well as production volume have been linked to cancer of the brain, bladder, colon, lung, breast, B-cell non-Hodgkin’s lymphoma, and adipocyte tumors.

Clinically, some variants in the structure of TNC may be a dominating predictor of how susceptible the cancer is to chemotherapy, the odds of the disease recurring and a poor prognosis. For some cancers, dramatically raised levels of TNC splice variants may be the link between inflammation and cancer development/progression ( TNC links to inflammation & cancer ). This may also involve the role of matrix metalloproteinases (MMPs), which are a family of proteins that degrade the matrix during inflammation, requiring subsequent remodeling and repair.

Indeed, in a recent large meta-analysis of 18 studies and 2732 cancer patients observed that elevated TNC levels was the most valuable metric for determining a poor cancer prognosis. The Hazard ratio as a predictor for survival was 1.73 and for lymph node metastasis, the odds ratio was 2.42 (TNC as a prognosticator of cancer survival ).

Another way of looking at it is: chemotherapy is designed to kill cancer cells but does not target the extracellular matrix and levels of Tenascin-C. Clearly it is possible, maybe even likely, that the cancer will return as the core problem driving cell proliferation (Tenascin-C) has not been targeted.

A matrix element that most have never heard of, Tenascin-C, is the best prognosticator of your chances of survival from a solid tumor cancer.

Retinitis Pigmentosa with Cataracts

Now for connecting a few dots in the medical literature. Research published this week, evaluated the aqueous humor of patients undergoing cataract surgery. Age-matched controls were compared to retinitis pigmentosa subjects and the proteomic analysis revealed dramatically elevated levels of TNC and its receptors on human lens epithelial cells in RP patients. Given the role of TNC in wound healing and tissue remodeling, the authors suggested that there may be a strong causal link between the pathogenesis of RP & levels of TNC, as has previously been proposed for TNC and cancer (RP & Raised TNC levels ).

It is intriguing to speculate that this association between TNC and RP may extend into an increased risk for brain cancer. Both the retina and central nervous system lie behind blood barriers (the Blood Retinal Barrier and the Blood Brain Barrier respectively). Light is a form of radiation which evokes the production of free radicals and redox-driven inflammation in the eye. Similar events are thought to contribute to the inception of brain cancer. Melanoma, another cancer featuring excessive growth & metastases of pigment cells (melanocytes) is also characterized by excessive TNC, as does RP.

It is possible that the underlying pathology in either case is a derangement in the form and/or amount of Tenascin-C.

Conclusion

Cancer and retinitis pigmentosa, the form of blindness commonly known as Tunnel Vision, are clearly quite different diseases. However, the purpose of this article was to draw attention to critical, common thread for both cancer and RP, which is the important role of Tenascin-C. This strange network between blindness, cancer and a matrix glycoprotein that is most commonly evident in embryo development, may be the portal to major breakthroughs in our fundamental understanding of how tissues repair without veering off into uncontrolled growth in cancer and RP, as well as many other conditions.

Dedication: This article is dedicated to my Mother, Patricia Mary Miller, an RP patient who died too young of a frontal-lobe glioma. The emerging science may be too late for my Mother, but maybe, just maybe, not too late for someone else’s Mother.