Oral and Intravenous Iron Therapy Differentially Alter the On- and Off-Tumor Microbiota in Anemic Colorectal Cancer Patients

Phipps, Oliver; Al-Hassi, Hafid O.; Quraishi, Mohammed Nabil; Dickson, Edward A; Segal, Jonathan; Steed, Helen; Kumar, Aditi; Acheson, Austin G; Beggs, Andrew D; Brookes, Matthew

doi:10.3390/cancers13061341

Cited by 12 publications

(15 citation statements)

References 48 publications

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“…With iron deficiency anemia tending to be unequally prevalent between right-and left-sided colorectal cancer patients, this may influence the differences observed in the tumor microbiota between locations [26]. As enteral iron therapy has been shown to alter the gut microbiota, this leaves the potential to present with differential bacterial populations compared to patients treated with parenteral iron, or those who are not iron deficient [13,16].…”

Section: Discussionmentioning

confidence: 99%

“…However, as subsequently discussed by Al-Hassi et al (2018), patients with right-sided colorectal tumors more commonly develop iron deficiency anemia relative to those with left-sided tumors, hence more often requiring iron therapy [12]. Enteral iron supplementation, often given to treat anemia, has been shown to alter the colonic microbiota, potentially through increasing gut luminal iron availability for bacterial cell proliferation [13]. The occurrence of iron deficiency anemia and the use of enteral iron supplementation was not assessed by the authors in the Flemer study and has the possibility to be accountable for differences observed [10].…”

Section: Introductionmentioning

confidence: 99%

“…All colorectal cancer patients included in this study had iron deficiency anemia and received parenteral iron therapy prior to surgery. Parenteral iron therapy was given in order to limit the influence of increasing gut iron concentration on the gut microbiota, associated with enteral iron therapy [13,16].…”

Section: Introductionmentioning

confidence: 99%

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Differences in the On- and Off-Tumor Microbiota between Right- and Left-Sided Colorectal Cancer

et al. 2021

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This study aims to determine differences in the on- and off-tumor microbiota between patients with right- and left-sided colorectal cancer. Microbiome profiling of tumor and tumor-adjacent biopsies from patients with right-sided (n = 17) and left-sided (n = 7) colorectal adenocarcinoma was performed using 16S ribosomal RNA sequencing. Off-tumor alpha and beta diversity were significantly different between right- and left-sided colorectal cancer patients. However, no differences in on-tumor diversity were observed between tumor locations. Comparing the off-tumor microbiota showed the right colon to be enriched with species of the Lachnoclostridium, Selenomonas, and Ruminococcus genera. Whereas the left colon is enriched with Epsilonbacteraeota phylum, Campylobacteria class, and Pasteurellales and Campylobacterales orders, in contrast, the on-tumor microbiota showed relatively fewer differences in bacterial taxonomy between tumor sites, with left tumors being enriched with Methylophilaceae and Vadin BE97 families and Alloprevotella, Intestinibacter, Romboutsia, and Ruminococcus 2 genera. Patients with left-sided colorectal cancer had large taxonomic differences between their paired on- and off-tumor microbiota, while patients with right-sided colorectal cancer showed relatively fewer taxonomic differences. Collectively, this suggests that the right and left colon show distinctive bacterial populations; however, the presence of a colonic tumor leads to a more consistent microbiota between locations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differences in the On- and Off-Tumor Microbiota between Right- and Left-Sided Colorectal Cancer

et al. 2021

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“…Osteosarcoma (OS) is the most prevalent form of malignancy affecting adolescents, occurring preferentially in males and developing at relatively high rates in individuals between the ages of 60 and 80 years [ 1 , 2 ]. While neoadjuvant chemotherapy has led to significant improvements in the duration of OS patient overall and disease-free survival (DFS), the survival of OS patients has plateaued in recent years [ 1 , 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

RhoA enhances osteosarcoma resistance to MPPa-PDT via the Hippo/YAP signaling pathway

Zhan

Chen

et al. 2021

Cell Biosci

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Background Osteosarcoma (OS) is the most prevalent primary bone malignancy affecting adolescents, yet the emergence of chemoradiotherapeutic resistance has limited efforts to cure affected patients to date. Pyropheophorbide-α methyl ester-mediated photodynamic therapy (MPPa-PDT) is a recently developed, minimally invasive treatment for OS that is similarly constrained by such therapeutic resistance. This study sought to explore the mechanistic basis for RhoA-activated YAP1 (YAP)-mediated resistance in OS. Methods The relationship between YAP expression levels and patient prognosis was analyzed, and YAP levels in OS cell lines were quantified. Immunofluorescent staining was used to assess YAP nuclear translocation. OS cell lines (HOS and MG63) in which RhoA and YAP were knocked down or overexpressed were generated using lentiviral vectors. CCK-8 assays were used to examine OS cell viability, while the apoptotic death of these cells was monitored via Hoechst staining, Western blotting, and flow cytometry. Tumor-bearing nude mice were additionally used to assess the relationship between lentivirus-mediated alterations in RhoA expression and MPPa-PDT treatment outcomes. TUNEL and immunohistochemical staining approaches were leveraged to assess apoptotic cell death in tissue samples. Results OS patients exhibited higher levels of YAP expression, and these were correlated with a poor prognosis. MPPa-PDT induced apoptosis in OS cells, and such MPPa-PDT-induced apoptosis was enhanced following YAP knockdown whereas it was suppressed by YAP overexpression. RhoA and YAP expression levels were positively correlated in OS patients, and both active and total RhoA protein levels rose in OS cells following MPPa-PDT treatment. When RhoA was knocked down, levels of unphosphorylated YAP and downstream target genes were significantly reduced, while RhoA/ROCK2/LIMK2 pathway phosphorylation was suppressed, whereas RhoA overexpression resulted in the opposite phenotype. MPPa-PDT treatment was linked to an increase in HMGCR protein levels, and the inhibition of RhoA or HMGCR was sufficient to suppress RhoA activity and to decrease the protein levels of YAP and its downstream targets. Mevalonate administration partially reversed these reductions in the expression of YAP and YAP target genes. RhoA knockdown significantly enhanced the apoptotic death of OS cells in vitro and in vivo following MPPa-PDT treatment, whereas RhoA overexpression had the opposite effect. Conclusions These results suggest that the mevalonate pathway activates RhoA, which in turn activates YAP and promotes OS cell resistance to MPPa-PDT therapy. Targeting the RhoA/ROCK2/LIMK2/YAP pathway can significantly improve the efficacy of MPPa-PDT treatment for OS.

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“…A recent study showed the supremacy of intravenous over per o s iron supplementation in mitigating inflammation around the tumor site by modulating the local microbial environment. The study included samples from 40 individuals, hence validation in larger cohorts is needed [ 74 ]. Nonetheless, the aforementioned studies indicate that even frequently prescribed medications such as antibiotics or iron supplementation need to be reconsidered in the context of microbiota-mediated CRC recurrence ( Figure 1 ).…”

Section: Microbiota In Crcmentioning

confidence: 99%

Resectable Colorectal Cancer: Current Perceptions on the Correlation of Recurrence Risk, Microbiota and Detection of Genetic Mutations in Liquid Biopsies

Koulouris

Tsagkaris

Messaritakis

et al. 2021

Cancers

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Metastatic colorectal cancer (mCRC) remains a highly lethal malignancy, although considerable progress has resulted from molecular alterations in guiding optimal use of available treatments. CRC recurrence remains a great barrier in the disease management. Hence, the spotlight turns to newly mapped fields concerning recurrence risk factors in patients with resectable CRC with a focus on genetic mutations, microbiota remodeling and liquid biopsies. There is an urgent need for novel biomarkers to address disease recurrence since specific genetic signatures can identify a higher or lower recurrence risk (RR) and, thus, be used both as biomarkers and treatment targets. To a large extent, CRC is mediated by the immune and inflammatory interplay of microbiota, through intestinal dysbiosis. Clarification of these mechanisms will yield new opportunities, leading not only to the appropriate stratification policies, but also to more precise, personalized monitoring and treatment navigation. Under this perspective, early detection of post-operative CRC recurrence is of utmost importance. Ongoing trials, focusing on circulating tumor cells (CTCs) and, even more, circulating tumor DNA (ctDNA), seem to pave the way to a promising, minimally invasive but accurate and life-saving monitoring, not only supporting personalized treatment but favoring patients’ quality of life, as well.

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Oral and Intravenous Iron Therapy Differentially Alter the On- and Off-Tumor Microbiota in Anemic Colorectal Cancer Patients

Cited by 12 publications

References 48 publications

Differences in the On- and Off-Tumor Microbiota between Right- and Left-Sided Colorectal Cancer

Differences in the On- and Off-Tumor Microbiota between Right- and Left-Sided Colorectal Cancer

RhoA enhances osteosarcoma resistance to MPPa-PDT via the Hippo/YAP signaling pathway

Resectable Colorectal Cancer: Current Perceptions on the Correlation of Recurrence Risk, Microbiota and Detection of Genetic Mutations in Liquid Biopsies

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