Neoadjuvant Chemotherapy Shifts Breast Tumor Microbiota Populations to Regulate Drug Responsiveness and the Development of Metastasis

127

In breast cancer (BC) the employment of sequencing technologies for metagenomic analyses has allowed not only the description of the overall metagenomic landscape but also the specific microbial changes and their functional implications. Most of the available data suggest that BC is related to bacterial dysbiosis in both the gut microenvironment and breast tissue. It is hypothesized that changes in the composition and functions of several breast and gut bacterial taxa may contribute to BC development and progression through several pathways. One of the most prominent roles of gut microbiota is the regulation of steroid-hormone metabolism, such as estrogens, a component playing an important role as risk factor in BC development, especially in postmenopausal women. On the other hand, breast and gut resident microbiota are the link in the reciprocal interactions between cancer cells and their local environment, since microbiota are capable of modulating mucosal and systemic immune responses. Several in vivo and in vitro studies show remarkable evidence that diet, probiotics and prebiotics could exert important anticarcinogenic effects in BC. Moreover, gut microbiota have an important role in the metabolism of chemotherapeutic drugs and in the activity of immunogenic chemotherapies since they are a potential dominant mediator in the response to cancer therapy. Then, the microbiome impact in BC is multi-factorial, and the gut and breast tissue bacteria population could be important in regulating the local immune system, in tumor formation and progression and in therapy response and/or resistance.

Section: Microbiota Anti-cancer Therapy and Disease Progressionmentioning

confidence: 83%

Breast and Gut Microbiota Action Mechanisms in Breast Cancer Pathogenesis and Treatment

Laborda-Illanes

Sánchez-Alcoholado

Domínguez-Recio

et al. 2020

127

“…Previously we showed that bacterial tryptophan metabolism is suppressed in early stages of breast cancer, releasing the brake on breast cancer cells [ 16 , 17 , 40 ]. In that sense, IS behaves similar to other cytostatic metabolites [ 16 , 17 , 25 , 32 , 39 , 40 , 41 , 42 , 43 , 45 , 46 ]. Of note, in addition to the loss of cytostatic properties, the breast cancer oncobiome has an increased capacity for reactive estrogens and increase estrogen enterohepatic circulation [ 1 , 93 ].…”

Section: Discussionmentioning

confidence: 88%

“…Furthermore, oncobiosis supports epithelial-to-mesenchymal transition (EMT) [ 16 , 17 , 40 , 44 ], migration and invasion [ 17 , 40 ], the reduction of oxidative stress [ 40 , 45 ], the proportions of ALDH1+ cancer stem cells [ 17 , 40 ], and widespread metabolic alterations [ 16 , 17 , 40 ] in cancers cells. These elementary steps are translated into enhanced tumor growth [ 16 , 17 ], aggressive tumor infiltration to the surrounding tissues [ 16 , 17 ], and enhanced metastasis formation [ 16 , 17 , 41 , 46 , 47 ].…”

Section: Introductionmentioning

confidence: 99%

Indoxylsulfate, a Metabolite of the Microbiome, Has Cytostatic Effects in Breast Cancer via Activation of AHR and PXR Receptors and Induction of Oxidative Stress

Sári

Mikó

Kovàcs

et al. 2020

Changes to bacterial metabolite-elicited signaling, in oncobiosis associated with breast cancer, plays a role in facilitating the progression of the disease. We show that indoxyl-sulfate (IS), a tryptophan metabolite, has cytostatic properties in models of breast cancer. IS supplementation, in concentrations corresponding to the human serum reference range, suppressed tumor infiltration to the surrounding tissues and metastasis formation in a murine model of breast cancer. In cellular models, IS suppressed NRF2 and induced iNOS, leading to induction of oxidative and nitrosative stress, and, consequently, reduction of cell proliferation; enhanced oxidative and nitrosative stress are crucial in the subsequent cytostasis. IS also suppressed epithelial-to-mesenchymal transition vital for suppressing cellular movement and diapedesis. Furthermore, IS rendered cells hypometabolic, leading to a reduction in aldehyde-dehydrogenase positive cells. Pharmacological inhibition of the pregnane-X receptor using CH223191 and the aryl-hydrocarbon receptor using ketoconazole diminished the IS-elicited effects, suggesting that these receptors were the major receptors of IS in these models. Finally, we showed that increased expression of the human enzymes that form IS (Cyp2E1, Sult1A1, and Sult1A2) is associated with better survival in breast cancer, an effect that is lost in triple negative cases. Taken together, IS, similar to indolepropionic acid (another tryptophan metabolite), has cytostatic properties and higher expression of the metabolic machinery responsible for the formation of IS supports survival in breast cancer.

“…A recent microbial analysis of breast tumors from untreated or neoadjuvant chemotherapy-treated patients showed chemotherapy-induced shifts in breast tumor microbiome with a significant increase in Pseudomonas spp. Moreover, the elevated abundance of Brevundimonas and Staphylococcus in patients' primary tumors was shown to be associated with the development of distant metastasis [78].…”

Section: Gut Microbiome Chemotherapy and Microbiota-modulated Efficmentioning

confidence: 99%

Exploring the Potential Role of the Gut Microbiome in Chemotherapy-Induced Neurocognitive Disorders and Cardiovascular Toxicity

Ciernikova

Mego

Chovanec

2021

Chemotherapy, targeting not only malignant but also healthy cells, causes many undesirable side effects in cancer patients. Due to this fact, long-term cancer survivors often suffer from late effects, including cognitive impairment and cardiovascular toxicity. Chemotherapy damages the intestinal mucosa and heavily disrupts the gut ecosystem, leading to gastrointestinal toxicity. Animal models and clinical studies have revealed the associations between intestinal dysbiosis and depression, anxiety, pain, impaired cognitive functions, and cardiovascular diseases. Recently, a possible link between chemotherapy-induced gut microbiota disruption and late effects in cancer survivors has been proposed. In this review, we summarize the current understanding of preclinical and clinical findings regarding the emerging role of the microbiome and the microbiota–gut–brain axis in chemotherapy-related late effects affecting the central nervous system (CNS) and heart functions. Importantly, we provide an overview of clinical trials evaluating the relationship between the gut microbiome and cancer survivorship. Moreover, the beneficial effects of probiotics in experimental models and non-cancer patients with neurocognitive disorders and cardiovascular diseases as well as several studies on microbiota modulations via probiotics or fecal microbiota transplantation in cancer patients are discussed.