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Microbiome in Cancer: Role in Carcinogenesis and Impact in Therapeutic Strategies

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 23172

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Dr. Rui Ferreira

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1. i3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
2. Ipatimup–Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
Interests: microbiome; metagenomics; metabolomics; gastric cancer
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Dear colleagues,

In recent years, due to the significant advances in next-generation sequencing technologies, our knowledge on the vast collection of microorganisms that lives in close association with humans has increased exponentially. Several lines of evidence suggest that microbial imbalance is associated with the development of cancer. Fine examples of this link can be observed for tissues routinely exposed to microorganisms, namely, those in the colon and stomach. On the other hand, compelling evidence now suggests that the microbiome can influence responses to anti-tumoral therapeutics. For example, the gut microbiome signatures of patients who respond to immunotherapy are associated with enhanced systemic immunity and increased intratumoral immune infiltration. Moreover, microbial communities within the tumour microenvironment can also contribute to the efficacy of other anti-cancer therapies and affect treatment-associated toxicity. Based on this knowledge, the microbiome has garnered interest as a cancer biomarker, but also as a target in the treatment of cancer.

This Special Issue aims to focus on the impact of the microbiome on cancer development and on the emerging role of microbial communities in the success of anti-cancer therapy.

Dr. Rui Ferreira
Guest Editor

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Keywords

microbiome
dysbiosis
microbes
microbiome as cancer biomarkers
cancer
cancer immune therapy
cancer chemotherapy

Published Papers (9 papers)

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Research

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23 pages, 2275 KiB

Open AccessArticle

Integrated Microbiota and Metabolite Changes following Rice Bran Intake during Murine Inflammatory Colitis-Associated Colon Cancer and in Colorectal Cancer Survivors

by Annika M. Weber, Hend Ibrahim, Bridget A. Baxter, Robin Kumar, Akhilendra K. Maurya, Dileep Kumar, Rajesh Agarwal, Komal Raina and Elizabeth P. Ryan

Cancers 2023, 15(8), 2231; https://doi.org/10.3390/cancers15082231 - 10 Apr 2023

Cited by 2 | Viewed by 2975

Abstract

Dietary rice bran-mediated inhibition of colon carcinogenesis was demonstrated previously for carcinogen-induced rodent models via multiple anti-cancer mechanisms. This study investigated the role of dietary rice bran-mediated changes to fecal microbiota and metabolites over the time course of colon carcinogenesis and compared murine fecal metabolites to human stool metabolic profiles following rice bran consumption by colorectal cancer survivors (NCT01929122). Forty adult male BALB/c mice were subjected to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated colon carcinogenesis and randomized to control AIN93M (n = 20) or diets containing 10% w/w heat-stabilized rice bran (n = 20). Feces were serially collected for 16S rRNA amplicon sequencing and non-targeted metabolomics. Fecal microbiota richness and diversity was increased in mice and humans with dietary rice bran treatment. Key drivers of differential bacterial abundances from rice bran intake in mice included Akkermansia, Lactococcus, Lachnospiraceae, and Eubacterium xylanophilum. Murine fecal metabolomics revealed 592 biochemical identities with notable changes to fatty acids, phenolics, and vitamins. Monoacylglycerols, dihydroferulate, 2-hydroxyhippurate (salicylurate), ferulic acid 4-sulfate, and vitamin B6 and E isomers significantly differed between rice bran- and control-fed mice. The kinetics of murine metabolic changes by the host and gut microbiome following rice bran consumption complemented changes observed in humans for apigenin, N-acetylhistamine, and ethylmalonate in feces. Increased enterolactone abundance is a novel diet-driven microbial metabolite fecal biomarker following rice bran consumption in mice and humans from this study. Dietary rice bran bioactivity via gut microbiome metabolism in mice and humans contributes to protection against colorectal cancer. The findings from this study provide compelling support for rice bran in clinical and public health guidelines for colorectal cancer prevention and control. Full article

(This article belongs to the Special Issue Microbiome in Cancer: Role in Carcinogenesis and Impact in Therapeutic Strategies)

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17 pages, 1591 KiB

Open AccessArticle

Microbiota of Urine, Glans and Prostate Biopsies in Patients with Prostate Cancer Reveals a Dysbiosis in the Genitourinary System

by Micael F. M. Gonçalves, Teresa Pina-Vaz, Ângela Rita Fernandes, Isabel M. Miranda, Carlos Martins Silva, Acácio Gonçalves Rodrigues and Carmen Lisboa

Cancers 2023, 15(5), 1423; https://doi.org/10.3390/cancers15051423 - 23 Feb 2023

Cited by 3 | Viewed by 1772

Abstract

Prostate cancer (PCa) is the most common malignant neoplasm with the highest worldwide incidence in men aged 50 years and older. Emerging evidence suggests that the microbial dysbiosis may promote chronic inflammation linked to the development of PCa. Therefore, this study aims to compare the microbiota composition and diversity in urine, glans swabs, and prostate biopsies between men with PCa and non-PCa men. Microbial communities profiling was assessed through 16S rRNA sequencing. The results indicated that α-diversity (number and abundance of genera) was lower in prostate and glans, and higher in urine from patients with PCa, compared to non-PCa patients. The different genera of the bacterial community found in urine was significantly different in PCa patients compared to non-PCa patients, but they did not differ in glans and prostate. Moreover, comparing the bacterial communities present in the three different samples, urine and glans show a similar genus composition. Linear discriminant analysis (LDA) effect size (LEfSe) analysis revealed significantly higher levels of the genera Streptococcus, Prevotella, Peptoniphilus, Negativicoccus, Actinomyces, Propionimicrobium, and Facklamia in urine of PCa patients, whereas Methylobacterium/Methylorubrum, Faecalibacterium, and Blautia were more abundant in the non-PCa patients. In glans, the genus Stenotrophomonas was enriched in PCa subjects, while Peptococcus was more abundant in non-PCa subjects. In prostate, Alishewanella, Paracoccus, Klebsiella, and Rothia were the overrepresented genera in the PCa group, while Actinomyces, Parabacteroides, Muribaculaceae sp., and Prevotella were overrepresented in the non-PCa group. These findings provide a strong background for the development of potential biomarkers with clinical interest. Full article

(This article belongs to the Special Issue Microbiome in Cancer: Role in Carcinogenesis and Impact in Therapeutic Strategies)

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14 pages, 4795 KiB

Open AccessArticle

Oral Microbiota as Novel Biomarkers for Colorectal Cancer Screening

by Sama Rezasoltani, Hamid Asadzadeh Aghdaei, Seyedesomaye Jasemi, Maria Gazouli, Nikolas Dovrolis, Amir Sadeghi, Hartmut Schlüter, Mohammad Reza Zali, Leonardo Antonio Sechi and Mohammad Mehdi Feizabadi

Cancers 2023, 15(1), 192; https://doi.org/10.3390/cancers15010192 - 28 Dec 2022

Cited by 15 | Viewed by 2732

Abstract

Alterations of the gut microbiome in cases of colorectal cancer (CRC) hint at the involvement of host–microbe interactions in the onset and progression of CRC and also, possibly, provide novel ways to detect and prevent CRC early. The aim of the present study was to evaluate whether the oral and fecal microbiomes of an individual can be suitable for CRC screening. Oral and fecal samples (n = 80) were gathered in Taleghani hospital, affiliated with Shahid Beheshti University of Medical Sciences, Tehran–Iran, from CRC stage 0 and I patients and healthy controls (HCs), who were screened for the first time. Microbial metagenomics assays were performed for studying microbiota profiles in all oral and fecal samples gathered. An abundance of top bacterial genera from both types of specimens (fecal and saliva samples) revealed a distinction between CRC patients and HCs. In saliva samples, the α diversity index was different between the microbiome of HCs and CRC patients, while β diversity showed a densely clustered microbiome in the HCs but a more dispersed pattern in CRC cases. The α and β diversity of fecal microbiota between HCs and CRC patients showed no statistically significant differences. Bifidobacterium was identified as a potential bacterial biomarker in CRC saliva samples, while Fusobacterium, Dialister, Catonella, Tennerella, Eubacterium-brachy-group, and Fretibacterium were ideal to distinguish HCs from CRC patients. One of the reasons for the heterogeneity of CRC may be the gastrointestinal (GI) tract microbiota, which can also cause systematic resistance to CRC. Moreover, an evaluation of saliva microbiota might offer a suitable screening test for the early detection of this malignancy, providing more accurate results than its fecal counterpart. Full article

(This article belongs to the Special Issue Microbiome in Cancer: Role in Carcinogenesis and Impact in Therapeutic Strategies)

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13 pages, 4318 KiB

Open AccessArticle

Luminal and Tumor-Associated Gut Microbiome Features Linked to Precancerous Lesions Malignancy Risk: A Compositional Approach

by Vladimir A. Romanov, Ivan A. Karasev, Natalia S. Klimenko, Stanislav I. Koshechkin, Alexander V. Tyakht and Olga A. Malikhova

Cancers 2022, 14(21), 5207; https://doi.org/10.3390/cancers14215207 - 24 Oct 2022

Cited by 3 | Viewed by 2382

Abstract

Colorectal cancer is the third most commonly diagnosed cancer worldwide. Human gut microbiome plays important roles in protecting against it, as well as contributing to its onset and progression. Identification of specific bacterial taxa associated with early stages of colorectal cancer may help develop effective microbiome-based diagnostics. For precancerous lesions, links of their characteristics to luminal and tumor-associated microbiome composition are to be elucidated. Paired stool and tumor brush biopsy samples were collected from 50 patients with precancerous lesions and early forms of colon cancer; their microbial communities were profiled using high-throughput 16S rRNA sequencing. We showed that the microbiome differences between stool and biopsy samples can be to a high extent computationally corrected. Compositionality-aware statistical analysis of microbiome composition revealed its associations with the number of lesions, lesion type, location and malignization pathway. A major determinant of precancerous lesions malignancy risk—the number of lesions—was positively associated with the abundance of H₂S-producing taxa. Our results contribute to the basis for developing early non-invasive colorectal cancer diagnostics via identifying microorganisms likely participating in early stages of cancer pathogenesis. Full article

(This article belongs to the Special Issue Microbiome in Cancer: Role in Carcinogenesis and Impact in Therapeutic Strategies)

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21 pages, 5851 KiB

Open AccessArticle

Live Biotherapeutic Lactococcus lactis GEN3013 Enhances Antitumor Efficacy of Cancer Treatment via Modulation of Cancer Progression and Immune System

by Sujeong Kim, Yunjae Kim, Suro Lee, Yulha Kim, Byungkwan Jeon, Hyerim Kim and Hansoo Park

Cancers 2022, 14(17), 4083; https://doi.org/10.3390/cancers14174083 - 23 Aug 2022

Cited by 10 | Viewed by 2766

Abstract

The gut microbiota is responsible for differential anticancer drug efficacies by modulating the host immune system and the tumor microenvironment. Interestingly, this differential effect is highly strain-specific. For example, certain strains can directly suppress tumor growth and enhance antitumor immunity; however, others do not have such an effect or even promote tumor growth. Identifying effective strains that possess antitumor effects is key for developing live biotherapeutic anticancer products. Here, we found that Lactococcus lactis GEN3013 inhibits tumor growth by regulating tumor angiogenesis and directly inducing cancer cell death. Moreover, L. lactis GEN3013 enhanced the therapeutic effects of oxaliplatin and the PD-1 blockade. Comprehensive immune profiling showed that L. lactis GEN3013 augmented cytotoxic immune cell populations, such as CD4⁺ T cells, CD8⁺ effector T cells, and NK cells in the tumor microenvironment. Our results indicate that L. lactis GEN3013 is a promising candidate for potentiating cancer treatment in combination with current standard therapy. Full article

(This article belongs to the Special Issue Microbiome in Cancer: Role in Carcinogenesis and Impact in Therapeutic Strategies)

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15 pages, 1773 KiB

Open AccessArticle

Unraveling the Risk Factors and Etiology of the Canine Oral Mucosal Melanoma: Results of an Epidemiological Questionnaire, Oral Microbiome Analysis and Investigation of Papillomavirus Infection

by Joyce Pires de Carvalho, Marcella Collaneri Carrilho, Denner Santos dos Anjos, Carolina Dagli Hernandez, Laura Sichero and Maria Lúcia Zaidan Dagli

Cancers 2022, 14(14), 3397; https://doi.org/10.3390/cancers14143397 - 13 Jul 2022

Cited by 5 | Viewed by 1929

Abstract

Oral mucosal melanoma (OMM) is the most common oral cancer in dogs and is very aggressive in this species; its risk factors and etiology are yet to be determined. This study aimed to unravel the risk factors for the development of OMM in dogs and to investigate the possible presence of papillomaviruses as an etiological factor. A case-control study was conducted in 15 dogs with OMM and 15 paired controls whose owners answered an epidemiological questionnaire. Oral swabs from the same dogs were subjected to 16S rRNA sequencing for microbiome analyses. In addition, DNA fragments of OMM had their DNA extracted and amplified by polymerase chain reaction in an attempt to detect canine papillomaviruses. The gingiva was the most frequent anatomical site (47%) of OMM, and most tumors were stage III when diagnosed. Most dogs bearing OMM and the controls had grade 3 periodontal disease, and this factor, along with tartar treatment and tooth brushing, did not differ between cases and controls. Most dogs with OMM and most controls had contact with smokers; there was no statistically significant difference. Canine papillomaviruses were not detected among OMM cases. Tannerella forsythia and Porphyromonas gingivalis were significantly increased in case dogs compared to the controls. As these bacteria are reportedly involved in the pathogenesis of periodontal disease and esophageal cancer in humans, we suggest that they might be risk factors for the development of canine OMM. The limitations of this study include the low number of dogs, and therefore, further studies on canine OMM with larger numbers of animals are encouraged. Full article

(This article belongs to the Special Issue Microbiome in Cancer: Role in Carcinogenesis and Impact in Therapeutic Strategies)

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20 pages, 2470 KiB

Open AccessArticle

Skin Cancer-Associated S. aureus Strains Can Induce DNA Damage in Human Keratinocytes by Downregulating DNA Repair and Promoting Oxidative Stress

by Annika Krueger, Ahmed Mohamed, Cathryn M. Kolka, Thomas Stoll, Julian Zaugg, Richard Linedale, Mark Morrison, H. Peter Soyer, Philip Hugenholtz, Ian H. Frazer and Michelle M. Hill

Cancers 2022, 14(9), 2143; https://doi.org/10.3390/cancers14092143 - 25 Apr 2022

Cited by 10 | Viewed by 2522

Abstract

Actinic keratosis (AK) is a premalignant lesion, common on severely photodamaged skin, that can progress over time to cutaneous squamous cell carcinoma (SCC). A high bacterial load of Staphylococcus aureus is associated with AK and SCC, but it is unknown whether this has a direct impact on skin cancer development. To determine whether S. aureus can have cancer-promoting effects on skin cells, we performed RNA sequencing and shotgun proteomics on primary human keratinocytes after challenge with sterile culture supernatant (‘secretome’) from four S. aureus clinical strains isolated from AK and SCC. Secretomes of two of the S. aureus strains induced keratinocytes to overexpress biomarkers associated with skin carcinogenesis and upregulated the expression of enzymes linked to reduced skin barrier function. Further, these strains induced oxidative stress markers and all secretomes downregulated DNA repair mechanisms. Subsequent experiments on an expanded set of lesion-associated S. aureus strains confirmed that exposure to their secretomes led to increased oxidative stress and DNA damage in primary human keratinocytes. A significant correlation between the concentration of S. aureus phenol soluble modulin toxins in secretome and the secretome-induced level of oxidative stress and genotoxicity in keratinocytes was observed. Taken together, these data demonstrate that secreted compounds from lesion-associated clinical isolates of S. aureus can have cancer-promoting effects in keratinocytes that may be relevant to skin oncogenesis. Full article

(This article belongs to the Special Issue Microbiome in Cancer: Role in Carcinogenesis and Impact in Therapeutic Strategies)

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Review

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23 pages, 1114 KiB

Open AccessReview

The Role of the Microbiome on the Pathogenesis and Treatment of Colorectal Cancer

by Irene Yu, Rongrong Wu, Yoshihisa Tokumaru, Krista P. Terracina and Kazuaki Takabe

Cancers 2022, 14(22), 5685; https://doi.org/10.3390/cancers14225685 - 19 Nov 2022

Cited by 13 | Viewed by 2411

Abstract

The gut microbiome has long been known to play a role in various aspects of health modulation, including the pathogenesis of colorectal cancer (CRC). With immunotherapy recently emerging as a successful treatment in microsatellite instability high (MSI-high) CRC, and with a newly demonstrated involvement of the gut microbiome in the modulation of therapeutic responses, there has been an explosion of research into the mechanisms of microbial effects on CRC. Harnessing and reprogramming the microbiome may allow for the expansion of these successes to broader categories of CRC, the prevention of CRC in high-risk patients, and the enhancement of standard treatments. In this review, we pull together both well-documented phenomena and recent discoveries that pertain to the microbiome and CRC. We explore the microbial mechanisms associated with CRC pathogenesis and progression, recent advancements in CRC systemic therapy, potential options for diagnosis and prevention, as well as directions for future research. Full article

(This article belongs to the Special Issue Microbiome in Cancer: Role in Carcinogenesis and Impact in Therapeutic Strategies)

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13 pages, 1458 KiB

Open AccessReview

The Crosstalk between Microbiome and Immunotherapeutics: Myth or Reality

by Alireza Tojjari, Hassan Abushukair and Anwaar Saeed

Cancers 2022, 14(19), 4641; https://doi.org/10.3390/cancers14194641 - 24 Sep 2022

Cited by 2 | Viewed by 2031

Abstract

The gut microbiome refers to microorganisms and their genetic material influencing local and systemic inflammation. Inflammation is known to contribute to cancer development, progression, and treatment. Evidence suggests that modulating the gut microbiome may affect responses to various cancer therapies. The gut microbiota has been suggested to have an impact on immunotherapy efficacy, especially the currently widely used immune checkpoint inhibitors in various malignancies. Microbial interventions like fecal microbiota transplantation, various probiotics, or even antibiotics can increase or decrease the tumor’s sensitivity to immunotherapy. However, not all tumors react in the same manner, highlighting the tumor microenvironment heterogeneity across tumor types and the influence this has on the crosstalk between the microbiome and therapy outcomes. In this study, we intend to review the association between the gut microbiota and immunotherapy response in cancer patients and the factors regulating this interaction. Full article

(This article belongs to the Special Issue Microbiome in Cancer: Role in Carcinogenesis and Impact in Therapeutic Strategies)

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