Scientific Creativity, Courage, and Cancer

A mid star-laden galas and beautiful people events, we continually declare victories in the “war against cancer,” but let’s take a hard look at morbidity and mortality data across a daunting spectrum of pathology about which there is just enough common ground that we can unite it under a few broad descriptors such as “angiogenesis.”

Despite the latest science and technology, despite efforts at early detection and aggressive multidimensional intervention, despite the authoritative what to eat/what to drink/how to exercise algorithms, the clinical reality is this: human beings with cancer have experienced a small decline in mortality rate (approximately 1.5% since 1975) while experiencing the same ineluctable outcomes today (NCI 2015). So the overarching question remains: what do we need to do differently? One thing is instantly clear: we cannot be sluggish in the face of oncologic and public health impotence.

What we can infer with some certainty is that there is a soup of angiogenic growth and signaling factors that exist in the vascular compartment courtesy of the microbiome, and that these may spill over into and involve myeloid cell types as well. It was only 25 years ago that a discussion about the microbiome and health implications was received with considerable skepticism. The NIH-sponsored Human Microbiome Project (HMP) continues to characterize the microbiome leveraging metagenomic sequencing approaches (NIH HMP Working Group et al., 2009). Modulation of the human microbiome has been implicated in numerous health outcomes, including possible reduced cancer risk (Bultman 2014).

We cannot afford to be circumspect or shy about theorizing etiologic pathways and the associated therapeutic trials. To quote Edward de Bono, “There is no doubt that creativity is the most important human resource of all. Without creativity, there would be no progress, and we would be forever repeating the same patterns.” Whether we term this courage or creativity or equal measures of each, the point is crystal clear.

Let us examine one more time the original Folkman hypothesis advanced in 1971. The hypothesis was based on accumulating phosphoproteomic evidence that tyrosine kinases can be directly angiogenic or play a prominent role in the process of tumor vascularization. Let us acknowledge that bacterial receptor and cytoplasmic tyrosine kinases exist in theoretically available vast quantities, and that they have the capacity to function as angiogenins (Gotink and Verheul 2010; Grangeasse et al. 2012; Maywood 2003; Hooper et al. 2003; and Stappenbeck et al. 2002).

There seems more than enough evidenced-based medicine and clinical experience to suggest that baseline commensal populations of the microbiome, along with the spectrum of foods and medications that influence the gut microflora, should be studied carefully with an eye to exploring angiogenic mechanisms in various tissues.

We now know with some certainty that there are multiple mechanisms that tumors in various tissues and sites invoke to provide their vascularization, including hypoxia-triggered gene expression and myeloid cell inhibition (Rivera and Bergers 2015). If the common thread among these mechanisms is the microbiome, then this entity of 100 trillion organisms must at least be surveilled rigorously and systematically as a contributant to cancer etiology or progression.

If selected strains of lactobacillus, streptococcus, and bifidobacteria and their respective fermentation supernatants produce angiogenic inhibition, then relatively simple molecular biology could yield highly specific blocking antibodies that might be tested at various stages of angiogenic activity.

Admittedly, the experimental leap is across a wide scientific and clinical gap. Essentially one can posit angiogenins in substance and in quantity that investigators have not fully demonstrated or yet characterized. However, there is sufficient information from studies with gnotobiotic animals that provide a probabilistic foundation (Kulka et al. 2009; Hooper et al. 2003; Stappenbeck et al. 2002). Given the “bypass mechanisms” others have suggested to explain the rapid recovery of tumors from transitory suppression achieved following administration with tumor-derived angiogenins, further research is warranted.

While our emphasis has been unabashedly on cancer, it would be foolish to ignore the other side of the coin, i.e., the prospect of stimulating efficacious collateral vasculature in conditions where this is actually indicated. Previously, this writer and others have speculated about graft, flap, and wound healing applications, ischemic myocardium, and other physiologic conditions in which apparent pro-inflammatory and pro-angiogenic bacterial components and metabolites are desired. The science is not out of the realm of practicality, and the fertile research and development areas for food science and for the food industry seem to highlight their own relevance, timeliness, and scientific courage.

Roger Clemens, DrPH, CFS, Contributing Editor
Adjunct Professor, Univ. of Southern California School of Pharmacy, Los Angeles, Calif.
[email protected]