Refers to article: http://science.sciencemag.org/content/357/6356/1156.full
Data in the paper, Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine
Gemcitabine – Wikipedia is a Nucleoside analogue – Wikipedia used to treat cancers such as breast, bladder, lung and pancreas.
The authors (1) first explored how some tumor cell lines became resistant to gemcitabine, finding it to be associated with some kind of filter- and antibiotic-susceptible entity, identifying that entity to be Mycoplasma hyorhinis – Wikipedia. Next, the authors found not just Mycoplasma but 13 of 27 different bacterial species tested to be capable of mediating gemcitabine resistance in cancer cell lines, with this capacity mostly but not always matching capacity to express the long form of the Cytidine deaminase – Wikipedia (CDD).
Having established a connection between presence of bacteria and capacity for gemcitabine resistance, the authors then examined whether there were bacteria in human tumors, choosing to focus on Pancreatic cancer – Wikipedia (PDAC) since gemcitabine is a critical Rx for it.
Quantitative Real-time polymerase chain reaction – Wikipedia to detect bacterial 16S ribosomal RNA – Wikipedia detected bacterial rDNA in 86 of 113 (76%) PDAC and 3 of 20 (15%) normal pancreas. Authors confirmed these results with additional assays such as Fluorescence in situ hybridization – Wikipedia (FISH) targeting 16S rRNA as well as Immunohistochemistry – Wikipedia using antibody to detect bacterial Lipopolysaccharide – Wikipedia (LPS).
52% of the bacteria were Gammaproteobacteria – Wikipedia, most belonging to Enterobacteriaceae – Wikipedia and Pseudomonadaceae – Wikipedia families.
Finally, authors cultured bacteria from 15 fresh human PDACs and found 14 of 15 capable of making the RKO and HCT116 human colon carcinoma cells fully resistant to gemcitabine.
Article’s main message is selective association of particular bacteria with the human tumor, PDAC, with such association being capable of conferring tumor resistance to the anti-cancer drug, gemcitabine. More than one other group (2, 3) has previously reported such bacterial (Mycoplasma) ability to alter anti-cancer nucleoside function.
Caveats to the study are mainly technical and don’t negate its main message.
- What is by now a standard refrain in so many biomedical research papers (even those published in high impact factor journals such as Science), shoddy use of statistics to present data, especially from in vivo mouse models, as cleaner and much more dichotomous than they actually are. For example, a lack of consistency in the statistical tools used to summarize the data, being standard deviation in one figure, standard error of the mean in another, as well as the interchangeable use of the terms technical and biological replicates.
- Having gone to some lengths to emphasize that bacterial expression of the long form of CDD was required for gemcitabine resistance, authors provide no explanation for mechanism of gemcitabine resistance in M. hyorhinis, which the authors themselves point out expresses the short, not long, form of CDD. Clearly, different bacteria likely have more than one mechanism for mediating gemcitabine resistance.
How Bacteria Might Home To & Grow Within Cancers
Growth within solid tumors typically entails destructive features. Though Neovascularization – Wikipedia, growth of new, disorganized and leaky blood vessels, crops up to support the ravenous oxygen and nutrient demand of such rapidly proliferating cancer cells, such demand more often than not outpaces supply with two major consequences.
Such leaky and disorganized vasculature could make it possible for circulating bacteria to gain access to tumor tissue while hypoxic tumor tissue, being a favorable growth environment for anaerobic bacteria (both obligate and facultative), becomes a magnet for such bacteria, which enter such regions and get settled there.
Further, more than usual number of cells dying in an unplanned manner within solid tumors typically overwhelms the local scavenging capacity of clean-up cells belonging to the local reticuloendothelial system (Mononuclear phagocyte system – Wikipedia) that would normally clear up the resulting cell carcasses and debris. This makes such areas pools of not only chemical messengers that could attract bacteria but also of nutrients that could sustain them (see below from 4).
Thus, not just one but several studies have reported presence of bacteria within solid tumors (see below from 4).
Link Between Mycoplasma & Solid Tumors
Among the smallest of bacteria and lacking a cell wall, association of Mycoplasma in particular with tumors is of an interesting piece within this sub-field of tumor biology, having been reported as far back as 1970 (5).
- Cancer cell lines are notorious for becoming infected with Mycoplasma so much so numerous reviews outline how to prevent and eliminate such contamination (6, 7, 8, 9). Such cancer cell-Mycoplasma associations also have practical cost consequences. Since basic research can and often is sloppy enough that Mycoplasma contaminations may even pass unnoticed in some labs, which published responses pertain to cancer cell and which to the Mycoplasma associated with it is a real issue that remains unresolved (10, 11, 12).
- A 1999 study (13) by researchers at the American Registry of Pathology at the Armed Forces Institute of Pathology showed chronic colonization of cell lines with Mycoplasma fermentans and M. penetrans to be associated with chromosomal instability and malignant transformation, i.e., potentially carcinogenic capacities.
- A 2001 PCR-based study (14) found Mycoplasma consistently and preferentially associated in different types of tumor tissues (see below from 15 using data from 14).
Mycoplasma proclivity for cancer cell lines grown in lab cell cultures is itself an intriguing phenomenon deserving of basic research interest since it occurs in absence of the plausible factors proffered for such association in vivo, such as disorganized and leaky blood vessels messily sprouting up to supply ravenously growing tumor tissue, and the lack of attendant tumor hypoxia and necrosis, factors supposed to make solid tumors a magnet for bacterial (Mycoplasma) growth.
The Contentious History of Bacteria in Tumors
Presence of bacteria in tumors has a particularly contentious past in scientific research. After research by Louis Pasteur – Wikipedia and Robert Koch – Wikipedia, among many others, firmly established a scientific basis for the Germ theory of disease – Wikipedia, several prominent mid-20th century researchers tenaciously pursued presence of bacteria in tumors.
The focus of such research by scientists such as Virginia Livingston – Wikipedia, Eleanor Alexander-Jackson, Irene Diller, Florence B. Seibert – Wikipedia was nothing less than trying to uncover evidence that an infectious disease agent underlay any and all types of cancer, i.e., a germ theory of cancer.
However, while some viral, even bacterial and other microbial causes of cancer are certainly known and accepted, the germ theory of cancer became markedly unfashionable over the course of the latter part of the 20th century in the face of the considerable headwind gained by other mechanisms of Carcinogenesis – Wikipedia, which took increasing precedence, principally mechanisms involving the interplay between overexpression an/or mutations in Oncogene – Wikipedia and mutations in Tumor suppressor gene – Wikipedia.
Bacteria as sole cause of cancer is also difficult to reconcile with the fact that Germ-free animal – Wikipedia do develop cancers. Thus, today only one bacterium, Helicobacter pylori is recognized by the International Agency for Research on Cancer – Wikipedia (IARC) as an established human carcinogen (16).
However, consequence of such single-minded focus by one group of researchers trying to prove a germ theory of cancer and severe repudiation of the same by others that followed them may have been detrimental in the long run, detrimental since it seems to have firmly shut the door for at least several decades on a more open-minded exploration of the association between bacteria and cancer, and consequences thereof. After all, a more open-minded view suggests research and therapeutic utility, be such association cause or effect (see below from 17, emphasis mine),
‘Microbial profiling of cancer is agnostic as to whether bacteria are the cause or the effect, although in each scenario lies clinical utility. If the development of cancer is the underlying reason for shifts in the microbial community, then surveying bacteria becomes a new method for diagnosis. Microbial censuses could be used to diagnose malignancies and in surveillance for recurrence. Of clinical importance is that microbiome sampling, as opposed to blood sampling or tissue biopsies, is generally non-invasive. Such approaches are already revealing insights; for example, specific microbes in saliva have been associated with chronic pancreatitis and tumors of the pancreas . On the other hand, if shifts in the microbial spectrum cause cancer, then not only does microbiome research become a new route into exploring pathogenesis but the microbiome itself becomes a new target for preventative strategies. Microbiomes could be sampled proactively for risk stratification in at-risk populations, and probiotics and microbiome transplants could be considered as strategies for cancer prevention.
Also intriguing is the idea that one might be able to categorize cancers that do or do not have a microbial influence. It has been demonstrated in head and neck cancers that microbes live deep within tumor tissue , thus contributing to the intracellular stromal environment. Unless their borders are breached by infection, organs such as the kidney and the pancreas have been thought to be completely sterile. With modern metagenomic profiling, which can identify fastidious and previously unculturable microorganisms, we might find that fewer organ systems are sterile than previously thought, and that the contribution of the microbial microenvironment might have a much more inward reaching influence than currently assumed. Classifying cancers into sterile and non-sterile, if sterile cancers truly exist, might garner increased biological understanding of tumorigenesis, perhaps providing new avenues for diagnosis and even novel treatment modalities for nonsterile cancers’
1. Geller, Leore T., et al. “Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.” Science 357.6356 (2017): 1156-1160. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine
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