Might tumor secreted cathepsin proteases leave specific molecular signals in skin, hair and nails years before a cancer becomes clinically apparent?

The early detection of cancers by physical examination, body fluid analyses, endoscopies, various imaging procedures, cytology and biopsy is critical for timely treatment and future prognosis. X-ray fiber diffraction analysis (FDA) of hair, nails and skin , remote from the site of the cancer, has been demonstrated to non-invasively diagnose various cancers with a high degree of sensitivity and specificity, sometimes years before the cancer becomes clinically apparent.

Unfortunately, the technology has not been widely accepted because of reproducibility issues, and perhaps the lack of a biological explanation as to how a clinically unapparent cancer can result in molecular signals in hair, nails and skin remote from the site of the cancer. However, with the proper technique of FDA, the reproducibility issues should be readily resolved.

Moreover, we believe that tumor secreted cathepsin proteases might be the missing biological link that explains how cancers can leave specific molecular ‘‘signatures” in remote tissues long before they are diagnosed.

X-ray fiber diffraction analysis (FDA)

Fibrous biological macromolecules, such as keratin in hair and nails, and collagen in the dermal layer of skin, are readily studied by FDA; details of the technique are described in the literature. Tissues are made of fibrous macromolecules; the polymeric structures either run parallel intrinsically, such as a-keratin plates in nails, or are mechanically induced into parallel configuration by stretching the collagen fibrils in the dermal layer of the skin.

The oriented fibers are situated in a collimated X-ray beam with the parallel fibers at right angles to the beam and the pattern of X-ray diffraction at low angles is analyzed and recorded. Importantly, FDA reveals specific diffraction ring patterns for different cancer types.

Interestingly, breast and colon cancer can be diagnosed by FDA of hair, nails and skin; by contrast, prostate, ovarian, and lung cancer can be diagnosed by FDA of skin, but not by FDA of hair nor nails. Notably, skin punch biopsies are typically 3 mm in size and much less invasive than standard trans-rectal prostate biopsies. So, how might clinically undiagnosed and unapparent cancers, lead to distinctive molecular ‘‘signatures” in hair, nails and skin, as evidenced by tumor specific fiber diffraction ring patterns seen on FDA.

Cathepsin proteases and cancer

Cathepsins are lysosomal proteases that act as crucial effector and regulatory molecules and as such are involved in a myriad of biological processes . They are highly expressed in a variety of cancers and other cell types including tumor-associated macrophages, and are actively involved in the degradation of the extracellular matrix (including collagen), cell proliferation, angiogenesis, modulation of signaling pathways, tissue invasion, and metastasis.

There are at least a dozen different cathepsins, and the function of individual cathepsins vary considerably among different tumor types. Although cathepsins are concentrated locally, they indeed circulate systemically, and measuring cathepsins in serum has become a tool for non-invasively assessing tumor malignancy potential. For example, the serum concentration of cathepsin B has been positively correlated with the aggressiveness and progression of prostate cancer.

Many, but not all cathepsins, exhibit reduced proteolytic activity outside of the acidic tumor environment; accordingly, it is noteworthy that cathepsin S maintains its optimal proteolytic activity at a neutral pH. It is particularly interesting that observational data from an older population (age 71 at baseline) have demonstrated that baseline serum cathepsin S concentrations correlated positively and significantly with both cardiovascular mortality (p = 0.01) and cancer mortality (p = 0.01) over 12.6 years of observation.

In fact, the association between the baseline serum cathepsin S concentration and cancer mortality remained robust even after excluding subjects with prevalent cancer at baseline and those who developed cancer in the first 2 years of follow-up. This intriguing finding suggests that cathepsins are released systemically a number of years by cancer cells before a tumor is clinically diagnosed.


We hypothesize that cathepsins, specific for each cancer type, are released systemically by tumors long before they become clinically apparent, and over time, by virtue of their proteolytic activity, leave molecular ‘‘signatures” in keratin and collagen. Those subtle molecular signals are translated into tumor specific ring patterns evidenced by FDA of hair, nails, and/or skin, depending upon specific tumor type. Furthermore, it has been shown that the FDA ring patterns revert to normal after the successful treatment of the tumor.

X-ray fiber diffraction analysis of hair, nails and particularly skin can be a safe and non-invasive means to diagnose various cancers early, and monitor the treatment of the cancer. We call for more research to be done with FDA, its technical reproducibility, and tumor specific cathepsins in the early diagnosis and treatment of a variety of cancers. Finally, this could revolutionize both the diagnosis and treatment of cancer.


Author: Mark R. Goldstein, Luca Mascitelli

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