Could the Tumour Microbiome be the Next Generation of Cancer Treatment?

By Ellie Fung

With the many findings of its significant contributions to health and disease, the human microbiome has been studied extensively for its potential as a novel target for disease diagnosis and treatment. While studies of gut bacteria have dominated much of microbiome research, microbial communities have also been detected in tumours, prompting speculation that bacteria may influence oncogenesis and cancer progression. 

Distinct bacterial communities were detected in skin, colorectal and pancreatic cancers, sites with high exposure to a residing microbiota or external bacteria (Kostic et al., 2012; Matson et al., 2018; Pushalkar et al., 2018). Quantitative PCR and 16s rDNA gene sequence analyses demonstrated an abundance of Fusobacteria and few Bacteroidetes and Firmicutes in colorectal carcinomas compared with healthy tissue (Kostic et al., 2012), while human pancreatic ductal adenocarcinomas (PDAC) showed enriched Proteobacteria, Synergistetes and Euryarchaeota (Pushalkar et al., 2018). In the latter, researchers demonstrated that bacteria may promote oncogenesis in mouse models. PDAC-bearing mice were given oral antibiotics before the faecal microbiota transplantation (FMT) of feces from either wild-type or PDAC-bearing mice. Tumour growth accelerated to previous levels in the mice that received feces from PDAC-bearing mice, while mice with wild-type faecal donors were protected against cancer progression, possibly via the induction of immune suppression by the microbiome. It was also shown that antimicrobial treatments upregulate gene expression for T-cell proliferation and immune activation, implicating the microbiome’s role in mediating cancer progression. 

Similarly, Riquelme et al. (2019) revealed a significant positive correlation between T-cell activation in PDAC tissues and intratumoural microbiome diversity, suggesting the microbiome composition influences immunogenicity, though definite causality is yet to be established. Supporting this, FMT from long-term and short-term survivors of resected pancreatic cancer, followed by tumour inoculation, into germ-free mice showed that the tumour microbiome may confer immune protection against cancer and significantly slow tumour growth. Moreover, analysis of resected PDAC tumour microbiomes suggests that microbial signatures may be predictive of survival outcome: long-term survivor microbiomes were enriched with classes Alphaproteobacteria, Sphingobacteria and Flavobacteria, while Clostridia and Bacteroidea were predominant in short-term survivors. The researchers hence proposed that the microbiome could predict survivorship and be manipulated for cancer therapy. 

Despite these exciting findings, much of tumour microbiome research relies on FMT in rodent models, a relatively new methodology that lacks standardisation. A common pitfall, for instance, is increasing the number of mouse recipients without increasing human donors to obtain a statistically significant result. Such pseudo-replication inflates the number of false-positives and consequently misleading claims (Walter et al., 2020). The lack of scientific rigour in microbiome experimental design may thus threaten the overall credibility of the field. The use of rodent model in itself is also highly problematic, as colonisation in recipients may not represent communities in the native environment, or even if they do, the natural host-microbe interactions may not be replicated. Overall, FMT neglects the co-evolution between microbial communities and their native hosts that has occurred over millennia. While the recent findings of distinct intratumour microbiomes and their potential roles in mediating cancer progression and therapy are indeed stimulating, enthusiasm and sensationalism should not overshadow the need for critical analysis into the underlying experimental methods, lest jeopardising scientific integrity. 

Shifting away from FMT, a recent survey of tumour microbiomes characterised bacterial communities in different cancer types, including in sites that were less studied, such as breast, brain and bone cancers. The reliability of previous attempts to characterise communities at these sites was questioned as the low bacterial biomass in samples was highly prone to contamination (Atreya & Turnbaugh, 2020). Nejman et al. (2020) mitigated this concern by processing human solid tumour samples with over 600 negative controls and 6 strictly enforced filters, a method considered to be the most comprehensive and rigorous as of late (Atreya & Turnbaugh, 2020). With a novel 5R 16S rRNA sequencing method, Nejman et al. supported previous studies finding intratumoural compositions to be distinct to that of normal tissues. Benefitting from the use of a single sequencing technology, they were able to directly compare the microbiota of different cancer types to demonstrate that each type has a unique microbial signature with distinctive bacterial load and composition. They found bacteria to be localised to cancer cells, with adjacent tissues showing a significantly lower level. Intriguingly, localisation was also seen in immune cells. 

In agreement with previous studies, they found that the tumour microenvironment of melanomas in responders and non-responders of immunotherapy differed significantly at the taxon level while the overall bacterial load remained similar. The group further suggested that tumours create a niche for certain bacteria, as taxa found in the same cancer types display common functional traits that reflected the tumour microenvironment. As an example, 17 of 49 metabolic pathways that were enriched in current smokers’ lung tumours, are involved in degradation of chemicals found in cigarette smoke. In line with earlier researchers, they highlighted the potential of the tumour microbiome in cancer therapy developments.  

Despite providing detailed profiles of tumour microbiomes, the survey leaves much to be answered. It does not attempt to mechanistically explain the role and origins of the tumour microbiome, nor does it determine whether intratumoural bacteria plays a causal role in cancer progression or whether host-microbe interactions exist (Atreya & Turnbaugh, 2020). More advanced research is required to fully understand the mechanisms behind the tumour microenvironment and its effects on the host. The challenge now lies in finding a truly representative research model and in establishing standardised study protocols to avoid extrapolation and false positives (Walter et al., 2020). Overcoming this obstacle may allow the hopes of novel cancer diagnostics and therapeutics to come into fruition. For now, the human tumour microbiome remains a mystery. 

References:

Atreya, C. E. & Turnbaugh, P. J. (2020) Probing the tumor micro(b)environment. Science. 368 (6494), 938. Available from: doi: 10.1126/science.abc1464. 

Kostic, A. D., Gevers, D., Pedamallu, C. S., Michaud, M., Duke, F., Earl, A. M., Ojesina, A. I., Jung, J., Bass, A. J., Tabernero, J., Baselga, J., Liu, C., Shivdasani, R. A., Ogino, S., Birren, B. W., Huttenhower, C., Garrett, W. S. & Meyerson, M. (2012) Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Research. 22 (2), 292-298. Available from: doi: 10.1101/gr.126573.111.

Matson, V., Fessler, J., Bao, R., Chongsuwat, T., Zha, Y., Alegre, M., Luke, J. J. & Gajewski, T. F. (2018) The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients. Science. 359 (6371), 104. Available from: doi: 10.1126/science.aao3290. 

Nejman, D., Livyatan, I., Fuks, G., Gavert, N., Zwang, Y., Geller, L. T., Rotter-Maskowitz, A., Weiser, R., Mallel, G., Gigi, E., Meltser, A., Douglas, G. M., Kamer, I., Gopalakrishnan, V., Dadosh, T., Levin-Zaidman, S., Avnet, S., Atlan, T., Cooper, Z. A., Arora, R., Cogdill, A. P., Khan, M. A. W., Ologun, G., Bussi, Y., Weinberger, A., Lotan-Pompan, M., Golani, O., Perry, G., Rokah, M., Bahar-Shany, K., Rozeman, E. A., Blank, C. U., Ronai, A., Shaoul, R., Amit, A., Dorfman, T., Kremer, R., Cohen, Z. R., Harnof, S., Siegal, T., Yehuda-Shnaidman, E., Gal-Yam, E., Shapira, H., Baldini, N., Langille, M. G. I., Ben-Nun, A., Kaufman, B., Nissan, A., Golan, T., Dadiani, M., Levanon, K., Bar, J., Yust-Katz, S., Barshack, I., Peeper, D. S., Raz, D. J., Segal, E., Wargo, J. A., Sandbank, J., Shental, N. & Straussman, R. (2020) The human tumor microbiome is composed of tumor type–specific intracellular bacteria. Science. 368 (6494), 973. Available from: doi: 10.1126/science.aay9189. 

Pushalkar, S., Hundeyin, M., Daley, D., Zambirinis, C. P., Kurz, E., Mishra, A., Mohan, N., Aykut, B., Usyk, M., Torres, L. E., Werba, G., Zhang, K., Guo, Y., Li, Q., Akkad, N., Lall, S., Wadowski, B., Gutierrez, J., Rossi, J. A. K., Herzog, J. W., Diskin, B., Torres-Hernandez, A., Leinwand, J., Wang, W., Taunk, P. S., Savadkar, S., Janal, M., Saxena, A., Li, X., Cohen, D., Sartor, R. B., Saxena, D. & Miller, G. (2018) The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discovery. 8 (4), 403-416. Available from: doi: 10.1158/2159-8290.CD-17-1134. 

Riquelme, E., Zhang, Y., Zhang, L., Montiel, M., Zoltan, M., Dong, W., Quesada, P., Sahin, I., Chandra, V., San Lucas, A., Scheet, P., Xu, H., Hanash, S. M., Feng, L., Burks, J. K., Do, K., Peterson, C. B., Nejman, D., Tzeng, C. D., Kim, M. P., Sears, C. L., Ajami, N., Petrosino, J., Wood, L. D., Maitra, A., Straussman, R., Katz, M., White, J. R., Jenq, R., Wargo, J. & McAllister, F. (2019) Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes. Cell. 178 (4), 795-806.e12. Available from: doi: https://doi.org/10.1016/j.cell.2019.07.008

Walter, J., Armet, A. M., Finlay, B. B. & Shanahan, F. (2020) Establishing or Exaggerating Causality for the Gut Microbiome: Lessons from Human Microbiota-Associated Rodents. Cell. 180 (2), 221-232. Available from: doi: https://doi.org/10.1016/j.cell.2019.12.025

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