The microbes in the gut have different effects on immunity and cancer through many different mechanisms. They can directly regulate cellular components that promote carcinogenesis. Successfully articulating and addressing these complexities will benefit scientists and clinicians with expertise in areas other than oncology to join cancer research careers, such as data science, mathematical modeling, neuroscience, inflammation and autoimmunity, aging, metabolism, endocrinology, and muscle physiology. Similar to the charity-based CRUK/NCI Cancer Grand Challenge programme, it specifically aims to encourage multidisciplinary collaboration to address the large number of questions described in this review.
Thrombosis, inflammation and cancer
Thromboembolism is the pathological formation of blood clots that block blood vessels. It is the leading cause of death in cancer patients and is associated with a poor prognosis that cannot be explained by the stage of the cancer. The risk of thrombosis in cancer patients is 9 times higher than in the general population, and the incidence of cancer-related thromboembolism is increasing.
The potential susceptibility to thrombosis is related to a dysregulated thromboinflammatory response involving interactions between coagulation and inflammatory mediators (Figure 1). Neutrophils are the most abundant myeloid leukocytes that promote thromboinflammation by releasing neutrophil-extracellular traps (NETs), a negatively charged combination of histones, proteolytic enzymes, and DNA that activates thrombosis. Several cancer types are known to secrete tissue factors, the main activators of blood clotting in the body. Higher levels of tissue factors in plasma are associated with worse cancer staging, worse prognosis, and risk of thrombosis. Thrombosis may promote tumor growth and spread. An elevated platelet count is a marker of poor prognosis and a risk of thromboembolism. Mouse models of GBM have shown that platelets bind to tumor cells via podophyllotin and, importantly, elevated plasma podophyllotin levels are associated with an increased risk of thromboembolism and reduced survival in patients.
Figure 1: Thrombosis, inflammation, and cancer
Studies in mice and humans have identified an association between the number and type of neutrophils within tumors and disease progression. The neutrophil phenotype is influenced by the environment, and many types of cancer cause potent immunosuppressive and proangiogenic functions of neutrophils, which promote tumor growth and/or spread. Balancing this view, emerging evidence also reveals the antitumor activity of neutrophils and tumor-derived factors that promote the education and activation of cytotoxic T cells. In addition to these functions, the release of NETs has been shown to promote the capture of tumor cells within the blood vessels, thereby facilitating metastasis, by physically protecting the tumor from the effects of cytotoxic T cells, or by remodeling its local microenvironment to awaken dormant cancer cells (Figure 1). Conversely, NETs can also be cytotoxic and have been shown to kill tumor cells through the action of associated proteolytic enzymes and histones.
Management of thrombosis
Many factors can alter the risk of thrombosis during the treatment of cancer patients, including surgery, chemotherapy, infection, and intravenous treatment drugs. A large-scale cohort study with continuous measurement of multiple biomarkers in treated cancer patients is needed to help identify risk biomarkers that can be used to define individual risk over time. Future assay development should look for reliable global markers of thrombosis risk in order to allow for a more flexible and personalized approach. This begs the question: once we can identify the risk, what can we do to mitigate it?
The use of low-dose anticoagulation (thromboprophylaxis) to prevent venous thromboembolism is effective in people at high risk of cancer. However, due to the risk of bleeding with this treatment, there is insufficient evidence to support the use of thromboprophylaxis in all cancer patients. Clinical scoring, the most effective being the Khorana score, can identify some, but not all, of the high risk. Newer anticoagulants, such as factor XI inhibitors, which aim to "decouple" hemostasis from thrombosis, are currently being trialled to treat cancer thrombosis (NCT05171075). Future randomised controlled trials should investigate its effectiveness in preventing thrombosis.
To improve the prognosis of cancer patients, we need to understand both the role of thromboinflammation and the development of methods to monitor thrombosis risk throughout cancer management to improve prevention and treatment strategies.
The Microbiome and Cancer: Disease Pathogenesis, Treatment Response, and Therapeutic Targeting
Another environmental complexity that goes beyond the host itself involves the human microbiome and its genomic composition. The microbiome has a different and profound impact on disease pathogenesis and treatment outcomes of human malignancies, and the polymorphic microbiome has recently been highlighted as a signature phenotypic feature of cancer. There is growing evidence of the impact of gut and other tissue microbiota on cancer pathogenesis and treatment response, as well as interesting effects on intratumoral microbiota.
The role of gut microbes in pathogenesis and treatment response
The microbes in the gut have different effects on immunity and cancer through many different mechanisms. They can directly modulate cellular components that promote carcinogenesis, for example, in colorectal cancer, and affect systemic and anti-tumor immunity. The importance of the gut microbiota in shaping immune checkpoint blockade responses was first shown in preclinical models and soon had landmark studies in human cohorts demonstrating the prognostic association of the gut microbiota with human cancer. Importantly, we are becoming increasingly aware of the taxonomic and functional characteristics of the gut microbiota that are associated with immunotherapy response and resistance, and data suggest that the presence of unfavorable taxa in the gut is associated with impaired systemic inflammation and anti-tumor immunity, as well as an increased risk of adverse events. Recent studies have also shown that dietary intake influences gut microbiota and immunotherapy response and toxicity, thus providing a manageable perspective for therapeutic interventions.
Targeting gut and tumor microbes for cancer treatment, interception, and prevention
A growing body of evidence supports modulating the microbiota as a strategy to enhance cancer treatment outcomes, including fecal microbiota transplantation or inoculation with well-defined mechanisms to guide microbial species. Other strategies include the elimination of tumor-promoting species within the TME by targeted antibiotic approaches. As we move forward, standardized methods must be developed to assess the distance of pathogenic (and beneficial) microorganisms from the intestinal and mucosal tissues where they naturally grow, as well as the distance from the inside of tumors. We must improve our understanding of the mechanisms of how gut and intratumoral microbes directly and indirectly influence cancer pathogenesis and thus patient outcomes.
prospect
Improving the longevity of cancer patients remains the primary goal of cancer research. Going forward, there are enormous but ultimately solvable challenges to improving quality of life and duration ("disease-free cancer"), reducing the burden of symptoms, and improving the sustainability, affordability, and accessibility of health care, through acceptance and a better understanding of the complex biology of disease, locally, and systems. Despite advances in our understanding of the disease, cancer incidence is estimated to increase by 20%-50% over the next 20 years, partly reflecting an aging population, an increase in obesity, and the multifaceted environmental factors that influence cancer onset and progression, a reality that requires continued investment and redoubling efforts to address its complexity. In addition, the incidence of early-onset cancers is increasing, and the reasons for this are unknown.
An overarching issue associated with a new era of addressing cancer complexity involves the systemic manifestations of disease and the effects of environmental exposures and influences – from recognized covert contamination to unhealthy diets, microbiota, and more – to the multi-step process of tumorigenesis, malignant progression, and therapeutic resistance in the human cancer spectrum. Successfully articulating and addressing these complexities will benefit scientists and clinicians with expertise in areas other than oncology to join cancer research careers, such as data science, mathematical modeling, neuroscience, inflammation and autoimmunity, aging, metabolism, endocrinology, and muscle physiology. This expansion of expertise and capacity will require new funding and research opportunities that cross disciplinary and international boundaries and go beyond traditional (primarily government) funding mechanisms, similar to the philanthropy-based CRUK/NCI Cancer Grand Challenge programme, specifically designed to encourage multidisciplinary collaboration to address the large number of issues described in this review.
At a time when the world's commitment to clinical academic training and subsequent career paths is under threat, there is an urgent need to reinvigorate clinical academic MD/PhD training programs, as well as medical postdoctoral research fellowships in lieu of formal doctorates, as well as innovative initiatives and funding mechanisms to "buy" protected time for physician-scientists to engage in translational research substantively.
The link between aging and cancer goes beyond the accumulation of mutations. Understanding how the organ/tissue and tumor landscape changes with age and different environmental exposures, and how these changes affect all stages of cancer evolution, from choosing a starting clone to metastasis, is critical to winning more battles and even cancer wars.
In the next two decades, as the world faces an aging population, cancer will reach at least one-third and the global incidence will rise, and it is hoped that the above analysis will help to provide a logical framework for initiatives aimed at addressing the complexities described in this article, aiming to increasingly prevent the occurrence of cancer, reduce the incidence of symptomatic cancer, and diagnose cancer earlier, collectively alleviating suffering and prolonging the quality of life and number of people suffering from this daunting disease.
Bibliography:
Embracing cancer complexity: Hallmarks of systemic disease: Cell