In a recently published perspective article, we reviewed novel and unresolved concepts related to the biology of cancer metastasis, that may be reasonably connected and resolved through the study of alterations in the gut microbiome.
There are unanswered questions in the field of cancer metastasis that we propose could be answered by looking at the impact of the intestinal microbiome in health and disease states. The questions we proposed in this review, with regards to the effects of intestinal dysbiosis in cancer metastasis include:
- Could gut microbiota-derived signals or cues trigger the break in metastatic dormancy?
- Are there patient specific features regulating the premetastatic niche and are these modulated by gut microbiota?
- Could the gut microbiome interaction with tumor cells through epigenomic/epigenetic regulation help predict metastatic proclivity?
There are numerous studies that have reported on the association between intestinal dysbiosis and the development of cancer, and the importance of the microbiome in the development of cancer. Intestinal dysbiosis is defined as an alteration in the composition and/or richness (i.e. the number of unique bacterial species) of the intestinal microbiota. It has been proposed that the microbiome is involved in the initiation and progression of various types of cancer, and that the tumor and tumor site themselves have a distinct microbiome in certain cancers. In addition, certain microbial agents or their products have been shown to have anticancer effects. Modulation of the microbiome has been shown to be helpful in the treatment of certain types of cancer. In spite of all of the evidence linking the intestinal microbiome with cancer, there remains a paucity of studies evaluating the effects of the microbiome and its product on the development or treatment of metastasis. In this paper we asked if the host contribution to trigger and regulate the cellular events of metastasis may involve the gut microbiota. As we propose this new research agenda, we hypothesize that modulation of the metastasis microenvironment resulting from gut microbiome alterations, influences the metastatic cascade.
Current Thoughts on Cancer Metastasis
Metastasis describes both the process of cancer spread (i.e., the verb) and the resultant secondary cancer lesion (i.e., noun). The process of metastasis involves microscopic tumor cells leaving the primary tumor. Through a variety of proposed mechanisms, cells pass through the tumor matrix and then through or between endothelial cells in order to enter the circulation. While in the circulation, tumor cells must resist anoikis (programmed cell death associated with loss of cellular contact), evade immune recognition, demonstrate metastatic endurance by coping with and adapting to a variety of cellular stresses, and either immediately proliferating or entering dormancy, and then breaking dormancy to subsequently proliferate within the distant organ. It is the lack of mechanistic clarity around triggers that break dormancy and the formation of the pre-metastatic niche that seem to be the most obvious link to a potential role of gut microbiota in modulating host immune responses and thus ultimately the development of tumor metastasis.
A clinical observation in several solid tumors includes late metastatic recurrence of a cancer despite complete resection of a primary tumor, and often following adjuvant chemotherapy. This clinical scenario has been explained by micrometastatic tumor cells, leaving the primary tumor, entering a relatively chemoresistant state associated with dormancy at distant organ sites or sanctuary sites (i.e., bone marrow), and then exiting this dormant state following an unknown trigger, to proliferate and yield late metastatic recurrent lesions. It remains unclear how the entry and exit from dormancy is regulated but postulated to include regulatory mechanisms involving both tumor cells and the cellular and stromal elements of the tumor microenvironment, potentially including elements of stress resistance described as metastatic endurance (see Figures 1 and 2).
Impact of Gut Microbiota on Stem Cell Traits
Based on the existing understanding of the roles of the gut microbiota inducing or mobilizing stem cells in the setting of wound healing and embryogenesis, it is reasonable to ask if similar events may serve as triggers or signals that may break the dormancy of micrometastatic cells. See the earlier-referenced article for a more detailed explanation of the interactions summarized in Figure 2.
In addition to the concept of dormancy over the past decade, several new areas of research in the field of metastasis have emerged. These new insights have been added to Stephen Paget’s 1889 explanation for the apparently non-random preference that certain cancers have for growth at certain secondary sites. Briefly, Paget’s seed and soil hypothesis suggested that the sites where metastases occur are defined not only by the tumor cell (“seed”) but also the microenvironment of the secondary metastatic site (“soil”). Recent data has shed new light on interaction between the seed and soil. Interestingly, the formation of the friendly metastatic tumor microenvironment (i.e. the soil) can precede the arrival of metastatic cells through mobilization of bone marrow-derived cells to form the so-called pre-metastatic niche at the secondary site. It is interesting to consider that recruitment of cells forming the premetastatic niche may be coordinated through alterations in the gut microbiota in similar ways to those observed with the gut microbiome regulating wound healing and stem cell trafficking.
Upon arrival at a distant site, the new microenvironment encountered by the metastatic cell is considered foreign and hostile. Survival of metastatic cells at the secondary site is likely a consequence of intrinsic features of the metastatic cell and an ability to effectively engage in a molecular cross-talk with its surroundings and in so doing modulate the environment of the secondary site to allow cell survival in the setting of stress. This engagement can occur by several mechanisms that we have collectively coined as metastatic endurance, which is also linked to the process of metastatic dormancy. Could the microbiome, through its effects on the immune system and production of metabolites, influence the pathways that lead to survival of metastatic cells?
Effects of Microbiota on Chronic Systemic Inflammation, and Link to Cancer Metastasis
The microbiota are involved in limiting systemic inflammation in the healthy state and contributing to systemic inflammation when intestinal dysbiosis is present. Chronic systemic inflammation has been shown to lead to the development of many diseases, including cancer development and progression. Distinct of this we now propose a rationale to consider the association between intestinal dysbiosis and the biology of cancer metastasis. There are multiple tumor types in which it has been shown that high serum C-reactive protein (CRP) and inflammatory cytokines increase the risk of recurrence and metastasis. Further evaluation of markers of inflammation may help to answer some of the unknown questions surrounding intestinal dysbiosis and its connection to cancer metastasis in general and some of the more novel and less understood components of the metastatic cascade.
Gut Microbiota-derived Metabolites and Possible Linkage to Metastasis
Are there certain metabolites produced by the gut microbiota that could be contributing to the break from metastatic dormancy, development of the premetastatic niche or epigenetic regulation of the metastatic tumor cells? (See Figure 3). The basis of this hypothesis is found in the role those bacterial metabolites play in oncogenesis and their role in post transcriptional regulation.
It has been proposed that the effects of specialized metabolites may explain current knowledge gaps in linking the gut microbiota to biological host mechanisms in various disease states, including cancer. We now propose that these or other metabolites may influence metastasis progression.
The questions that will need to be addressed in future studies include:
- What are the cellular phenotypes involved and how are they regulated?
- What are the bioactive metabolites produced in dysbiosis, and what are their targets?
- Are there metabolites from the microbiota that are involved in establishing a premetastatic niche, triggering the end of dormancy, or promoting a tumor microenvironment interaction?
- Are there secreted bioactive metabolites that contribute to vasculogenesis, angiogenesis, or epigenetic regulation of metastatic tumor cells?
Proposal for Development of a Novel Dysbiosis Blood Test
The intestinal microbiome acts as a functioning organ with a variety of interactions with the mammalian body. It will be through analysis of metabolites and other blood biomarkers that we will continue to gain insight into the function of the microbiome, and its effects in health and disease. In addition to identifying the specific bacteria that contribute to carcinogenesis, the identification of the mediators through which these bacteria promote cancer is essential to advance therapeutic interventions. For further elaboration on this important topic, please reference the published article.
Possible Future Therapeutic Applications
The mechanisms by which the microbiota may influence metastasis and the break in dormancy may uncover therapeutic and prognostic tools useful in improving outcomes for cancer patients. It has already been shown that manipulation of GI microbiota can improve cancer therapeutic responses. In the paper, we discuss a rationale for using the dog as a model for human disease with regards to the microbiome. Future studies will be required to provide a deeper understanding and characterization of the metagenome and metabolome of dogs in healthy and diseased states. After additional baseline data is established in health and disease, we will then be able to evaluate the effects of specific dietary and other therapeutic interventions.