Vitamin D, gut microbiota, and radiation-related resistance: a love-hate triangle
Identifieur interne : 000234 ( Pmc/Corpus ); précédent : 000233; suivant : 000235Vitamin D, gut microbiota, and radiation-related resistance: a love-hate triangle
Auteurs : Ruixue Huang ; Jing Xiang ; Pingkun ZhouSource :
- Journal of Experimental & Clinical Cancer Research : CR [ 0392-9078 ] ; 2019.
Abstract
Radiation resistance is a serious issue in radiotherapy. Increasing evidence indicates that the human gut microbiome plays a role in the development of radiation resistance. Vitamin D is an important supplement for cancer patients treated with radiotherapy. Against this background, this paper reviewed research regarding the associations among vitamin D, microbiota dysbiosis, and radiation resistance. A hypothesis is developed to describe the relationships among vitamin D, the gut microbiota, and radiotherapy outcomes. Radiotherapy changes the composition of the gut microbiota, which in turn influence the serum level of vitamin D, and its distribution and metabolism in the body. Alteration of vitamin D level influences the patient response to radiotherapy, where the underlying mechanisms may be associated with the intestinal microenvironment, immune molecules in the intestines, gut microbiome metabolites, and signaling pathways associated with vitamin D receptors. Our understanding of the contribution of vitamin D and the gut microbiota to radiotherapy outcomes has been increasing gradually. A better understanding of the relationships among vitamin D, the gut microbiota, and radiotherapy outcomes will shed more light on radiation resistance, and also promote the development of new strategies for overcoming it, thus addressing an important challenge associated with the currently available radiotherapy modalities for cancer patients.
Url:
DOI: 10.1186/s13046-019-1499-y
PubMed: 31843023
PubMed Central: 6915920
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PMC:6915920Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Vitamin D, gut microbiota, and radiation-related resistance: a love-hate triangle</title><author><name sortKey="Huang, Ruixue" sort="Huang, Ruixue" uniqKey="Huang R" first="Ruixue" last="Huang">Ruixue Huang</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0379 7164</institution-id><institution-id institution-id-type="GRID">grid.216417.7</institution-id><institution>Department of Occupational and Environmental Health,</institution><institution>Xiangya School of Public Health, Central South University,</institution></institution-wrap>Changsha, 410078 Hunan Province China</nlm:aff></affiliation></author><author><name sortKey="Xiang, Jing" sort="Xiang, Jing" uniqKey="Xiang J" first="Jing" last="Xiang">Jing Xiang</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0379 7164</institution-id><institution-id institution-id-type="GRID">grid.216417.7</institution-id><institution>Department of Occupational and Environmental Health,</institution><institution>Xiangya School of Public Health, Central South University,</institution></institution-wrap>Changsha, 410078 Hunan Province China</nlm:aff></affiliation></author><author><name sortKey="Zhou, Pingkun" sort="Zhou, Pingkun" uniqKey="Zhou P" first="Pingkun" last="Zhou">Pingkun Zhou</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8653 1072</institution-id><institution-id institution-id-type="GRID">grid.410737.6</institution-id><institution>Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory,</institution><institution>School of Public Health, Guangzhou Medical University,</institution></institution-wrap>Guangzhou, 511436 People’s Republic of China</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1803 4911</institution-id><institution-id institution-id-type="GRID">grid.410740.6</institution-id><institution>Department of Radiation Biology, Beijing Key Laboratory for Radiobiology,</institution><institution>Beijing Institute of Radiation Medicine,</institution></institution-wrap>AMMS, Beijing, 100850 China</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31843023</idno><idno type="pmc">6915920</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915920</idno><idno type="RBID">PMC:6915920</idno><idno type="doi">10.1186/s13046-019-1499-y</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000234</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000234</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Vitamin D, gut microbiota, and radiation-related resistance: a love-hate triangle</title><author><name sortKey="Huang, Ruixue" sort="Huang, Ruixue" uniqKey="Huang R" first="Ruixue" last="Huang">Ruixue Huang</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0379 7164</institution-id><institution-id institution-id-type="GRID">grid.216417.7</institution-id><institution>Department of Occupational and Environmental Health,</institution><institution>Xiangya School of Public Health, Central South University,</institution></institution-wrap>Changsha, 410078 Hunan Province China</nlm:aff></affiliation></author><author><name sortKey="Xiang, Jing" sort="Xiang, Jing" uniqKey="Xiang J" first="Jing" last="Xiang">Jing Xiang</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0379 7164</institution-id><institution-id institution-id-type="GRID">grid.216417.7</institution-id><institution>Department of Occupational and Environmental Health,</institution><institution>Xiangya School of Public Health, Central South University,</institution></institution-wrap>Changsha, 410078 Hunan Province China</nlm:aff></affiliation></author><author><name sortKey="Zhou, Pingkun" sort="Zhou, Pingkun" uniqKey="Zhou P" first="Pingkun" last="Zhou">Pingkun Zhou</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8653 1072</institution-id><institution-id institution-id-type="GRID">grid.410737.6</institution-id><institution>Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory,</institution><institution>School of Public Health, Guangzhou Medical University,</institution></institution-wrap>Guangzhou, 511436 People’s Republic of China</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1803 4911</institution-id><institution-id institution-id-type="GRID">grid.410740.6</institution-id><institution>Department of Radiation Biology, Beijing Key Laboratory for Radiobiology,</institution><institution>Beijing Institute of Radiation Medicine,</institution></institution-wrap>AMMS, Beijing, 100850 China</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Experimental & Clinical Cancer Research : CR</title><idno type="ISSN">0392-9078</idno><idno type="eISSN">1756-9966</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Radiation resistance is a serious issue in radiotherapy. Increasing evidence indicates that the human gut microbiome plays a role in the development of radiation resistance. Vitamin D is an important supplement for cancer patients treated with radiotherapy. Against this background, this paper reviewed research regarding the associations among vitamin D, microbiota dysbiosis, and radiation resistance. A hypothesis is developed to describe the relationships among vitamin D, the gut microbiota, and radiotherapy outcomes. Radiotherapy changes the composition of the gut microbiota, which in turn influence the serum level of vitamin D, and its distribution and metabolism in the body. Alteration of vitamin D level influences the patient response to radiotherapy, where the underlying mechanisms may be associated with the intestinal microenvironment, immune molecules in the intestines, gut microbiome metabolites, and signaling pathways associated with vitamin D receptors. Our understanding of the contribution of vitamin D and the gut microbiota to radiotherapy outcomes has been increasing gradually. A better understanding of the relationships among vitamin D, the gut microbiota, and radiotherapy outcomes will shed more light on radiation resistance, and also promote the development of new strategies for overcoming it, thus addressing an important challenge associated with the currently available radiotherapy modalities for cancer patients.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lin, L" uniqKey="Lin L">L Lin</name></author><author><name sortKey="Yan, L" uniqKey="Yan L">L Yan</name></author><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y Liu</name></author><author><name sortKey="Yuan, F" uniqKey="Yuan F">F Yuan</name></author><author><name sortKey="Li, H" uniqKey="Li H">H Li</name></author><author><name sortKey="Ni, J" uniqKey="Ni J">J Ni</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ferlay, J" uniqKey="Ferlay J">J Ferlay</name></author><author><name sortKey="Colombet, M" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Exp Clin Cancer Res</journal-id><journal-id journal-id-type="iso-abbrev">J. Exp. Clin. Cancer Res</journal-id><journal-title-group><journal-title>Journal of Experimental & Clinical Cancer Research : CR</journal-title></journal-title-group><issn pub-type="ppub">0392-9078</issn><issn pub-type="epub">1756-9966</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31843023</article-id><article-id pub-id-type="pmc">6915920</article-id><article-id pub-id-type="publisher-id">1499</article-id><article-id pub-id-type="doi">10.1186/s13046-019-1499-y</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Vitamin D, gut microbiota, and radiation-related resistance: a love-hate triangle</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Ruixue</given-names></name><address><email>huangruixue@csu.edu.cn</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Xiang</surname><given-names>Jing</given-names></name><address><email>542343886@qq.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Zhou</surname><given-names>Pingkun</given-names></name><address><email>birm4th@163.com</email></address><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0379 7164</institution-id><institution-id institution-id-type="GRID">grid.216417.7</institution-id><institution>Department of Occupational and Environmental Health,</institution><institution>Xiangya School of Public Health, Central South University,</institution></institution-wrap>Changsha, 410078 Hunan Province China</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8653 1072</institution-id><institution-id institution-id-type="GRID">grid.410737.6</institution-id><institution>Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory,</institution><institution>School of Public Health, Guangzhou Medical University,</institution></institution-wrap>Guangzhou, 511436 People’s Republic of China</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1803 4911</institution-id><institution-id institution-id-type="GRID">grid.410740.6</institution-id><institution>Department of Radiation Biology, Beijing Key Laboratory for Radiobiology,</institution><institution>Beijing Institute of Radiation Medicine,</institution></institution-wrap>AMMS, Beijing, 100850 China</aff></contrib-group><pub-date pub-type="epub"><day>16</day><month>12</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>16</day><month>12</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>38</volume><elocation-id>493</elocation-id><history><date date-type="received"><day>4</day><month>11</month><year>2019</year></date><date date-type="accepted"><day>4</day><month>12</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s). 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Radiation resistance is a serious issue in radiotherapy. Increasing evidence indicates that the human gut microbiome plays a role in the development of radiation resistance. Vitamin D is an important supplement for cancer patients treated with radiotherapy. Against this background, this paper reviewed research regarding the associations among vitamin D, microbiota dysbiosis, and radiation resistance. A hypothesis is developed to describe the relationships among vitamin D, the gut microbiota, and radiotherapy outcomes. Radiotherapy changes the composition of the gut microbiota, which in turn influence the serum level of vitamin D, and its distribution and metabolism in the body. Alteration of vitamin D level influences the patient response to radiotherapy, where the underlying mechanisms may be associated with the intestinal microenvironment, immune molecules in the intestines, gut microbiome metabolites, and signaling pathways associated with vitamin D receptors. Our understanding of the contribution of vitamin D and the gut microbiota to radiotherapy outcomes has been increasing gradually. A better understanding of the relationships among vitamin D, the gut microbiota, and radiotherapy outcomes will shed more light on radiation resistance, and also promote the development of new strategies for overcoming it, thus addressing an important challenge associated with the currently available radiotherapy modalities for cancer patients.</p></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Radiation resistance</kwd><kwd>Gut microbiota</kwd><kwd>Vitamin D</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Background</title><p id="Par2">In 2017, the global death population caused by cancer reached 9 million, which was nearly twice the number in 1990 [<xref ref-type="bibr" rid="CR1">1</xref>]. In 2018, 18.1 million new cancer cases, and 9.6 million deaths from cancer, were reported worldwide [<xref ref-type="bibr" rid="CR2">2</xref>]. Numerous treatments are available for non-melanoma skin cancer patients, with radiotherapy being an efficacious and tissue-preserving non-surgical option [<xref ref-type="bibr" rid="CR3">3</xref>]. Radiotherapy is defined as the clinical use of ionizing radiation (IR), including α or γ rays, to induce DNA damage in all exposed cells to ultimately kill cancer cells or prevent cancer growth [<xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR5">5</xref>]. It can be used to eradicate certain cancers or reduce their likelihood of recurrence, and as a palliative treatment [<xref ref-type="bibr" rid="CR6">6</xref>]. Currently, approximately 60% of patients being treated for cancer in the United States have received radiotherapy. Despite the increasing clinical application of radiotherapy, the resistance of tumor cells to IR remains a significant obstacle [<xref ref-type="bibr" rid="CR7">7</xref>], potentially leading to relapse, a poor treatment response or poor prognosis [<xref ref-type="bibr" rid="CR8">8</xref>–<xref ref-type="bibr" rid="CR13">13</xref>]. Moreover, radiation resistance induces injury to tumor-adjacent tissues, resulting in disruption of normal physiological functions, as expressed in symptoms such as diarrhea and rectal bleeding [<xref ref-type="bibr" rid="CR14">14</xref>], and significantly increasing the subsequent risk of a number of adverse events including cardiovascular disorders, micronutrient deficiencies, and even secondary tumors, all of which typically decrease patient quality of life. The phenomenon of radiation resistance presents two challenges to the advancement of radiotherapy: (1) development of a mechanistic understanding of the factors underlying radiation resistance and the heterogeneity thereof; and (2) development of effective treatments, based on clinical and experimental molecular methods, to decrease side effects and overcome radiation resistance in cancer patients. Currently, despite the rapid development of new technologies, our understanding of, and ability to treat, cancer is still limited by many factors, including radiation resistance [<xref ref-type="bibr" rid="CR15">15</xref>]. The current perspective on resistance mechanisms, which is a complex process involving multiple genes, factors, and signaling pathways, points to an unmet need to examine novel factors, including the functional role of the gut microbiota. Additionally, utilizing a nutrient-focused approach in individual cancer patients may improve the likelihood of successful radiotherapy, a reduced rate of side effects, and long-lasting benefits. Against this background, this review discusses areas of mechanistic understanding that may benefit from a new perspective.</p><sec id="Sec2"><title>Radiation resistance-related mechanisms</title><p id="Par3">Ionizing radiation deposits energy and generates reactive chemical species along “tracks”, resulting in cytotoxic and genotoxic injury to DNA, including DNA double-strand breaks, and posing a challenge to cancer cell survival by inhibiting the proliferation thereof [<xref ref-type="bibr" rid="CR16">16</xref>]. Additionally, IR can induce cell cycle arrest, apoptosis, autophagy, and changes in the cellular microenvironment [<xref ref-type="bibr" rid="CR12">12</xref>, <xref ref-type="bibr" rid="CR17">17</xref>], which can in turn lead to radiation resistance. Cancer cells may develop mechanisms to escape cell cycle arrest, resist DNA damage-induced cell apoptosis, or alter the cancer microenvironment through cytokines [<xref ref-type="bibr" rid="CR18">18</xref>–<xref ref-type="bibr" rid="CR20">20</xref>]. The radiation resistance associated with these changes benefits cancer cells and renders radiotherapy less effective. Several signaling pathways contribute to cellular resistance against IR (Fig. <xref rid="Fig1" ref-type="fig">1</xref>) [<xref ref-type="bibr" rid="CR21">21</xref>]. Although radiation resistance-related molecular mechanisms have been intensively investigated, many questions remain unresolved. For example, does crosstalk exist between individual mechanisms, and are there genes and proteins important in multiple mechanisms? For example, some reports have identified genes and proteins involved in both IR-induced cell cycle checkpoints and autophagy [<xref ref-type="bibr" rid="CR22">22</xref>]. Are there other mechanisms that must be considered for a complete understanding of radiation resistance? Moreover, is there a single core regulator of multiple radiation resistance-related signaling pathways, active during all radiation resistance processes? [<xref ref-type="bibr" rid="CR23">23</xref>, <xref ref-type="bibr" rid="CR24">24</xref>].
<fig id="Fig1"><label>Fig. 1</label><caption><p>Signaling pathways involved into the radiation-induced resistance. The extensive studied signaling pathways consist of DNA damage repair pathway, inflammation pathway, hypoxic pathway</p></caption><graphic xlink:href="13046_2019_1499_Fig1_HTML" id="MO1"></graphic></fig></p></sec><sec id="Sec3"><title>Association between radiotherapy and gut microbiota</title><p id="Par4">The gut microbiota, i.e., the bacteria, archaea, viruses, and eukaryotic microbes residing primarily in the colon (but also in other organs including the lung and stomach) [<xref ref-type="bibr" rid="CR25">25</xref>], accounts for approximately 1 kg of human body weight, and includes more unique genes than the human genome [<xref ref-type="bibr" rid="CR26">26</xref>]. Over the past decade, rapid development of DNA and 16 s RNA sequencing technology has dramatically improved researchers’ ability to survey changes in gut microbiota in response to different stresses [<xref ref-type="bibr" rid="CR27">27</xref>]. Increasingly, reports have indicated that the gut microbiota plays a major role in the maintenance not just of intestinal homoeostasis, but of the overall health of the body [<xref ref-type="bibr" rid="CR28">28</xref>]. In particular, the dysbiotic gut microbiome seen in cancer radiotherapy patients, with altered microbial diversity and richness relative to that of healthy individuals, has been associated with the outcomes of cancer therapy [<xref ref-type="bibr" rid="CR29">29</xref>]. Recently, it has been shown that gut microbiota status is closely related to the response to radiotherapy. Many studies have discussed the effectiveness of radiotherapy for various types of cancer, and radiotherapy-related side effects, in the context of the gut microbiota. Tilg et al. recently reported a direct link between altered microbiota composition and the inflammatory status of patients with type 2 diabetes; decreased diversity of the intestinal microbiota may lead to a failure to maintain the intestinal barrier needed to prevent systemic dissemination of gut bacteria and associated chemical mediators [<xref ref-type="bibr" rid="CR30">30</xref>]. Daily ultraviolet radiation of skin is a typical source of 25-hydroxyvitamin D3 (25(OH)D3) in the human body. Previous studies reported that ultraviolet radiation was associated with a significant change in the beta-diversity of feces. Specifically, members of the phylum Firmicutes family, including <italic>Coprococcus</italic>, were enriched, whereas members of the phylum Bacteroidetes family, such as Bacteroidales, were depleted [<xref ref-type="bibr" rid="CR31">31</xref>].</p><p id="Par5">During the process of radiotherapy, gut microbiota including <italic>Lactobacillus acidophilus</italic>, <italic>L.casei</italic>, and <italic>Bifidobacterium</italic> spp. have been proven to reduce symptoms of radiation-induced gut toxicity, such as diarrhea [<xref ref-type="bibr" rid="CR27">27</xref>]. However, Barker et al.(2015)reported that radiotherapy altered the composition of the gut microbiota, breaking the intestinal barrier and causing apoptosis in intestinal crypts [<xref ref-type="bibr" rid="CR32">32</xref>], although other studies found no effect of radiation on the gut microbiota. For instance, Gosiewski et al. showed that therapeutic doses of radiation did not significantly affect <italic>Lactobacillus</italic> populations [<xref ref-type="bibr" rid="CR33">33</xref>]. Dysbiotic gut microbiome may be due to factors other than irradiation, such as heterogeneity among patients, including with respect to their daily diets, alcohol intake, and medication use. This highlights the challenges faced by studies of the association of the gut microbiota with radiation resistance seeking to answer the following important questions. Which taxa/phyla play the most dominant role in the development of radiation resistance? How are gut microbiota-derived signaling molecules generated, and how do they increase or suppress radiation sensitivity? How do factors such as nutrients induce gut microbiota changes, and how is this linked to radiation resistance?</p></sec><sec id="Sec4"><title>Vitamin D: role in biological processes</title><p id="Par6">Vitamin D comprises a group of fat-soluble secosteroids responsible for the absorption of essential trace elements, such as calcium, magnesium, and phosphate, and having roles inmultiple biological processes [<xref ref-type="bibr" rid="CR34">34</xref>], including cell growth, as well as in immune function and inflammation (reduction thereof). Vitamin D supplements are provided to treat or prevent many diseases, including deficiency-induced rickets and osteomalacia [<xref ref-type="bibr" rid="CR35">35</xref>, <xref ref-type="bibr" rid="CR36">36</xref>]. For example, clinically, the high incidence and poor prognosis of colorectal cancer has been found to be partly attributed to insufficient vitamin D [<xref ref-type="bibr" rid="CR37">37</xref>], and colorectal cancer patients with high levels of vitamin D have a lower risk of metastatic progression during neoadjuvant therapy before radical surgery [<xref ref-type="bibr" rid="CR37">37</xref>]. A meta-analysis by Van den Blink et al. reported that vitamin supplementation reduced radiation-related bone fractures and the risk of avascular necrosis in patients undergoing pelvic radiotherapy [<xref ref-type="bibr" rid="CR38">38</xref>]. Castro-Equiluz et al. recommended vitamin D as the most important nutrient for cancer patients treated with pelvic radiotherapy [<xref ref-type="bibr" rid="CR14">14</xref>]. Typically, the natural form of cholecalciferol is produced in the skin from dehydrocholesterol, with pre-vitamin D3 produced after ultraviolet irradiation. This process is essential for vitamin D biosynthesis in humans, although vitamin D can also be supplied via the diet. In the body, vitamin D is transported into the blood and metabolized in the liver, where it is then hydroxylated to produce the active form, 25-hydroxyvitamin D3 (25(OH)D3). Many cytochrome P-450 enzymes are involved in the conversion of vitamin D to 25(OH)D3, including CYP2R1, CYP27A1, and CYP2D25 [<xref ref-type="bibr" rid="CR39">39</xref>]. This active form of vitamin D has numerous biological effects, including inhibition of the epithelial-mesenchymal (EMT) transition in cancer cells; it also confers protection against cardiovascular disease and inflammatory bowel disease. 25(OH)D3 prevents the EMT in human peritoneal mesothelial cells through regulation of the Wnt/β-catenin signaling pathway [<xref ref-type="bibr" rid="CR40">40</xref>]. Hou et al. observed that 1α, 25(OH)2D3 suppressed the migration of ovarian cancer cells by inhibiting the EMT, suggesting that1α,25(OH)2D3 might have potential as a therapeutic agent for ovarian cancer [<xref ref-type="bibr" rid="CR41">41</xref>]. Furthermore, Findlay et al. showed that 1α,25(OH)2D3 enhanced radiation sensitivity in colorectal cancer cells through regulating the EMT [<xref ref-type="bibr" rid="CR42">42</xref>]. Higher plasma levels of 25(OH)D3 are associated with a decreased risk of highly aggressive prostate cancer [<xref ref-type="bibr" rid="CR43">43</xref>]. Mutation or deficiency of the genes and enzymes responsible for the transport or metabolism of 25(OH)D3 may alter its levels and functions [<xref ref-type="bibr" rid="CR43">43</xref>]. For instance, a mutation in CYP2R1, a key hydroxylase for 25(OH)D3 production, resulted in deficiency thereof, as well as symptoms of vitamin D-dependent rickets [<xref ref-type="bibr" rid="CR44">44</xref>]. In addition to its classic effects on calcium and bone homeostasis, vitamin D has other important roles in immune regulation and protection of the cardiovascular system [<xref ref-type="bibr" rid="CR45">45</xref>]. As reported in the review article by Aranow, vitamin D receptors are expressed on immune cells, including B cells, T cells, and antigen-presenting cells; this indicates that active vitamin D metabolites are synthesized by these cells, suggesting that vitamin D can modulate innate and adaptive immune responses. In turn, this suggests that the beneficial effects of vitamin D supplementation in deficient individuals with autoimmune disease may extend beyond the effects on bone and calcium homeostasis [<xref ref-type="bibr" rid="CR45">45</xref>]. Similarly, vitamin D has a putative protective role in the cardiovascular system [<xref ref-type="bibr" rid="CR46">46</xref>]. Growing evidence suggests that vitamin D levels are inversely associated with the risk of cardiovascular diseases, including ischemic heart disease, stroke, hypertension, blood lipids abnormalities, and obesity [<xref ref-type="bibr" rid="CR47">47</xref>]. However, some studies, including randomized controlled trials (RCTs), did not report significant effects of vitamin D supplementation on cardiovascular outcomes [<xref ref-type="bibr" rid="CR48">48</xref>], suggesting a need for further research. Current evidence indicates that vitamin D plays important roles in cardiovascular function, but more data are needed to establish causality. In this review, we focused on the underlying mechanisms of radiation resistance; thus, in the discussion below, we will address the following: (i) the association of vitamin D level with the risk of radiotherapy-induced side effects; (ii) the association of vitamin D level with radiation resistance; (iii) the effects of vitamin D on the integrity of the intestinal barrier, (iv) the effects of vitamin D on the gut microbiota; and (v) the effects of gut microbiota on vitamin D metabolism, distribution, and utilization.</p></sec><sec id="Sec5"><title>Vitamin D-mediated roles in radiation resistance</title><p id="Par7">Recently, there has been increasing concern regarding the role of vitamin D in preventing radiotherapy-induced side effects. Surrounding tissues may be damaged during radiotherapy, leading to IR-induced symptom including diarrhea and rectal bleeding [<xref ref-type="bibr" rid="CR14">14</xref>]. A study by Mukai et al. indicated that vitamin D supplementation was a significant factor in prolonged metastasis-free survival after preoperative chemoradiation therapy for patients with pancreatic ductal adenocarcinoma [<xref ref-type="bibr" rid="CR49">49</xref>]. Radiation dermatitis occurs frequently during radiation therapy in cancer patients, and vitamin D ointment is helpful for its prevention [<xref ref-type="bibr" rid="CR50">50</xref>]. In a case report, vitamin D supplementation prior to surgery and radiotherapy in a patient with recurrent breast cancer altered certain biological cancer markers, such as estrogen receptor, human epidermal growth factor receptor, and nuclear protein Ki67 [<xref ref-type="bibr" rid="CR51">51</xref>]. Moreover, an increasing body of evidence suggests that gut epithelial vitamin D receptor signaling pathways play an essential role in maintaining the integrity of the intestinal mucosa. Vitamin D deficiency is associated with the severity of radiation-induced proctitis in cancer patients [<xref ref-type="bibr" rid="CR52">52</xref>]. However, the mechanisms underlying the ability of vitamin D to decrease radiotherapy-induced side effects needs to be elucidated so that appropriate management guidelines and recommendations for cancer patients undergoing radiotherapy can be formulated. Sharma et al. found that 25(OH)D3, the hormonally active form of vitamin D [<xref ref-type="bibr" rid="CR53">53</xref>], promoted responses of non-small cell lung cancer to irradiation through induction of autophagy via the vitamin D receptor/TP53/AMPK signaling pathway [<xref ref-type="bibr" rid="CR54">54</xref>]. Another study asserted that vitamin D has the potential to improve genetic inhibition and increase sensitivity to radiation, by acting as a switch between cytoprotective and cytotoxic autophagy [<xref ref-type="bibr" rid="CR55">55</xref>]. Elegant studies have indicated that loss of the DNA repair protein 53BP1 results in resistance of breast cancer cells to radiation. The active form of vitamin D, 1α,25(OH)2D3, stabilizes 53BP1 levels in tumor cells, restoring them as efficiently as cathepsin L inhibitors, and ultimately contributing to increased genomic instability in response to radiation and reduced proliferation of cancer cells [<xref ref-type="bibr" rid="CR56">56</xref>].</p><p id="Par8">Strikingly, 25(OH)D3 is crucial for maintaining the intestinal barrier [<xref ref-type="bibr" rid="CR57">57</xref>]. The physical intestinal barrier, comprised of a thick mucus layer and the epithelium, plays a critical role in the defense against microbes, harmful foreign antigens, endotoxins, and toxic metabolites of bacteria, in addition to other environmental hazards entering the body via the diet. The importance of 25(OH)D3 in the gut has been demonstrated over the past decade. In brief, 25(OH)D3 binds vitamin receptors on intestinal cells and regulates the transcription of target genes, promoting gut health by maintaining immune homeostasis and suppressing inflammation and fibrosis (Fig. <xref rid="Fig2" ref-type="fig">2</xref>). Furthermore, decreased intestinal epithelial vitamin D receptor expression alters gut microbial homeostasis, resulting in less butyrate production and, by extension, chemically induced colitis in mice [<xref ref-type="bibr" rid="CR58">58</xref>]. In human studies, high-dose vitamin D<sub>3</sub> supplementation had a beneficial effect on the human gut microbiota, markedly reducing typical opportunistic pathogens and increasing phylotype richness [<xref ref-type="bibr" rid="CR59">59</xref>]. Butyrate, a byproduct of carbohydrate breakdown by microbiota, has a well-established role in preventing mucosal inflammation. Sun et al. showed that decreased expression of intestinal epithelial vitamin D receptors led to lower butyrate production and intestinal barrier inflammation [<xref ref-type="bibr" rid="CR60">60</xref>]. Vitamin D protects the intestinal barrier by regulating tight junction proteins and inhibiting intestinal apoptosis [<xref ref-type="bibr" rid="CR61">61</xref>]. Furthermore, vitamin D enhances innate immunity by inducing antimicrobial peptides, and regulates adaptive immunity by promoting anti-inflammatory T cells and cytokines [<xref ref-type="bibr" rid="CR61">61</xref>]. A review by Cantorna et al. suggested that vitamin D deficiency increases susceptibility to infection or injury of the gastrointestinal tract [<xref ref-type="bibr" rid="CR62">62</xref>]. Vitamin D enhances the ability of innate lymphoid cells to produce IL-22, suppresses IFN-γ and IL-17 release from T cells, and induces regulation of T cells in the mucosal tissues, modulating microbial communities in the gut to maintain the integrity of the intestinal barrier. Mandle et al. showed that vitamin D3 (1000 IU per day) significantly improved intestinal barrier function-related biomarkers, such as tight junction proteins claudin-1 (CLDN1), occludin (OCLD), and mucin-12 (MUC12), in patients with recurrent colorectal adenoma [<xref ref-type="bibr" rid="CR63">63</xref>]. Disruption of intestinal epithelial barrier homeostasis typically occurs due to altered composition of the gut microbiota [<xref ref-type="bibr" rid="CR64">64</xref>], and the interaction between vitamin D and the gut microbiota serves as a primary defense against radiation resistance.
<fig id="Fig2"><label>Fig. 2</label><caption><p>The molecular mechanism of Vitamin D’s role in the biological functions. 25(OH)D3, the major metabolite of vitamin D, binds vitamin receptors on intestinal cells and regulates the transcription of target genes, promoting gut health by maintaining immune homeostasis and suppressing inflammation and fibrosis</p></caption><graphic xlink:href="13046_2019_1499_Fig2_HTML" id="MO2"></graphic></fig></p><p id="Par9">Radiotherapy influences vitamin D levels. A recent gene expression study showed that mice exposed to IR exhibited lower expression levels of the CYP genes Cyp4f18 and Cyp4v3 [<xref ref-type="bibr" rid="CR65">65</xref>]. CYP4 proteins have been reported to metabolize vitamin D and play an essential role in the defense against environmental stressors, including radiation exposure [<xref ref-type="bibr" rid="CR66">66</xref>]. The involvement of vitamin D metabolism in radiation injury has been documented in several gene expression studies [<xref ref-type="bibr" rid="CR67">67</xref>]. The vitamin D metabolite calcitroic acid increased in mice after high dose rate (HDR) cesium-137 (137Cs) and strontium-90 (90Sr) (1.1 Gy/min to) [<xref ref-type="bibr" rid="CR67">67</xref>], whereas a low dose rate (LDR) (3.0 mGy/min) had no effect on this metabolite; this suggested that the effects on vitamin D metabolism differ by exposure level. However, studies in this area are limited, particularly those examining how radiotherapy influences the mechanisms of vitamin D metabolism.</p></sec><sec id="Sec6"><title>Effects of vitamin D-on the gut microbiota</title><p id="Par10">In addition to protecting the intestinal barrier, vitamin D may favorably alter the gut microbiota [<xref ref-type="bibr" rid="CR60">60</xref>], with evidence also emerging of its role in reducing the resistance of cancer cellsto radiation. In some human studies, high-dose vitamin D3 supplementation had a beneficial effect on human gut microbiota, markedly reducing typical opportunistic pathogen species including <italic>Pseudomonas, Escherichia,</italic> and <italic>Shigella,</italic> and increasing phylotype richness [<xref ref-type="bibr" rid="CR59">59</xref>]. An association between vitamin D and radiation resistance has also been posited, via alteration of the gut microbiota. Ferrer-Mayorga et al. showed that the vitamin D metabolite 1α,25-dihydroxyvitamin D3 inhibits colorectal cancer cell proliferation and promotes epithelial differentiation of colon cancer cell lines, thereby improving radiation sensitivity through altering the composition of intestinal microbiota communities [<xref ref-type="bibr" rid="CR68">68</xref>]. Some studies reported that vitamin D influenced the gut microbiome through activation of enteric bacteria vitamin D receptor signaling [<xref ref-type="bibr" rid="CR69">69</xref>, <xref ref-type="bibr" rid="CR70">70</xref>]. Commensal and pathogenic bacteria directly regulate colonic epithelial vitamin D receptor expression, which in turn negatively regulates bacteria-induced intestinal nuclear factor-kappa B activation [<xref ref-type="bibr" rid="CR71">71</xref>, <xref ref-type="bibr" rid="CR72">72</xref>]. Accordingly, vitamin D receptor gene mutations in humans should influence the intestinal microbiota. In vitamin D receptor knockout mice, <italic>Parabacteroides</italic> abundance was altered significantly [<xref ref-type="bibr" rid="CR73">73</xref>], <italic>Lactobacillus</italic> was depleted, and <italic>Clostridium</italic> and <italic>Bacteroides</italic> showed enrichment [<xref ref-type="bibr" rid="CR74">74</xref>]. Furthermore, vitamin D deficiency induces notable changes in the gut microbiota, including increased <italic>Helicobacter hepaticus</italic> and decreased <italic>Akkermansiamuciniphila</italic> population sizes [<xref ref-type="bibr" rid="CR75">75</xref>]. <italic>Lactobacillus sakei</italic> is known to have a radioprotective effect for the enteritis compared to conventional chemical agents with inherent toxicities [<xref ref-type="bibr" rid="CR76">76</xref>]. Intaking synbiotic powder containing <italic>Lactobacillus reuteri</italic> (108 CFU) reduce proctitis symptoms and improve quality of life by preventing rectal inflammation during radiotherapy for prostate cancer [<xref ref-type="bibr" rid="CR77">77</xref>]. Moreover, <italic>Bacteroides</italic> increased in radiation-exposed conventional microbiota, and <italic>H. hepaticus</italic> is known to induce colon cancer [<xref ref-type="bibr" rid="CR78">78</xref>]. <italic>A. muciniphila</italic> is also known to improve barrier function and metabolic health [<xref ref-type="bibr" rid="CR79">79</xref>]. These data indicate that one mechanism via which vitamin D protects against radiation resistance is through targeting the gut microbiota via the vitamin D receptor. Moreover, alterations of gut microbiota can be caused by vitamin D intake and other dietary components, rendering gut microbiota regulation by vitamin D complex. Further study is needed to uncover and confirm the mechanisms underlying the effects of vitamin Don the gut microbiota.</p><p id="Par11">Logically, altered gut microbiota should influence the vitamin D distribution and metabolism in the body. However, studies on the contribution of altered gut microbiota to these parameters are scarce. Bora et al. showed that germ-free mice infected with the pathogen <italic>C. rodentium</italic> exhibited decreased vitamin D and 25D absorption post infection [<xref ref-type="bibr" rid="CR80">80</xref>]. They also measured serum 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D levels before and 2 weeks after broad-spectrum antibiotic treatment; the levels of all three compounds were increased, which was attributed to the microbiota or antibiotic treatment [<xref ref-type="bibr" rid="CR81">81</xref>]. A recent study examined the effect of the gut microbiota on vitamin D metabolism [<xref ref-type="bibr" rid="CR80">80</xref>], and found that it inhibited fibroblast growth factor 23 and induced increased serum 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D levels. Some researchers have suggested that different gut microbiota signatures and alterations in vitamin D3 levels may be useful markers of disease in clinical practice, and that fecal vitamin D3 and gut microbiota composition could serve as biomarkers for diagnosis and follow-up [<xref ref-type="bibr" rid="CR82">82</xref>]. However, for effective interventions targeting the gut microbiome composition and vitamin D levels, further investigation is required, to determine the mechanisms underlying vitamin D regulation by the microbiota. Future studies should address the following questions. (i) What are the underlying mechanisms by which vitamin D regulates radiation resistance?; (ii) Are vitamin D levels regulated predominantly by one bacterial species, or by multiple, interacting species?; (iii) Environmental factors, including ultraviolet radiation, and lifestyle factors including reduced physical activity and insufficient consumption of vitamin D-rich foods, are involved in the alteration of gut microbiota and the etiology of vitamin D deficiency, and may also be important in radiotherapy outcomes; do these factors affect radiation resistance, and if so, how?</p><p id="Par12">There is a pressing need for further investigation of the relationships among environmental factors, lifestyle factors, vitamin D levels, gut microbiota, and radiation resistance, to promote the development of vitamin D-based clinical interventions targeting the microbiota for addressing radiation resistance.</p></sec><sec id="Sec7"><title>Relationships among vitamin D, gut microbiota, and radiation resistance</title><p id="Par13">To review the research on the relationships of vitamin D, gut microbiota, and radiotherapy outcomes as well as acknowledge the study trend regarding these three topics, we searched published literature by the Pubmed(<ext-link ext-link-type="uri" xlink:href="http://www.pubmed.com">www.pubmed.com</ext-link>) and grants funded by the US National Institutes of Health (NIH, <ext-link ext-link-type="uri" xlink:href="https://www.nih.gov/">https://www.nih.gov/</ext-link>) over the past decade. We selected both two websites since Pubmed includes almost the possible published studies as possible as it can across the world scientific community, while NIH provide the grants funded mainly from developed counties such as USA and other developing countries such as India and China. As shown in Fig. <xref rid="Fig3" ref-type="fig">3</xref>, between 2009 and 2018, the number of publications on vitamin D, gut microbiota, and radiotherapy gradually increased, although grants and funding for vitamin D research have been gradually decreasing; in each of the last 3 years, there were fewer than 100 grants (Fig. <xref rid="Fig3" ref-type="fig">3</xref>a,b). In contrast, grants and funding for gut microbiota and radiotherapy research have been increasing gradually each year, and peaked in 2018(Fig. <xref rid="Fig3" ref-type="fig">3</xref>c,d). The total funding for gut microbiota research in 2018 was almost $200,000,000, far greater than that for vitamin D ($40,000,000) and radiotherapy ($25,000,000) research (Fig. <xref rid="Fig3" ref-type="fig">3</xref>e,f). Overall, these data suggest that vitamin D, gut microbiota, and radiotherapy are receiving attention from both the scientific community and governments.
<fig id="Fig3"><label>Fig. 3</label><caption><p>Study attention and grants trends on the vitamin D, gut microbiota and radiation-induced resistance from 2009 to 2018. (<bold>a</bold>) literatures amount of study attention on the field of vitamin D. (<bold>b</bold>) grants number and funding amounts of vitamin D. (<bold>c</bold>). literatures amount of study attention on the field of gut microbiota. (<bold>d</bold>) grants number and funding amounts of gut microbiota. (<bold>e</bold>) literatures amount of study attention on the field of radiotherapy. (<bold>f</bold>) grants number and funding amounts of radiotherapy</p></caption><graphic xlink:href="13046_2019_1499_Fig3_HTML" id="MO3"></graphic></fig></p><p id="Par14">In summary, the relationships among vitamin D, gut microbiota, and radiotherapy outcomes can be described as a triangle, as illustrated in Fig. <xref rid="Fig4" ref-type="fig">4</xref>; the roles of the elements of this “love-hate triangle” differ according to the physiological/pathological status of the cell. Vitamin D plays a crucial role in protecting the intestinal barrier and preventing gastrointestinal mucosal inflammation. Vitamin D deficiency not only affects the integrity of the barrier, but also moderates the composition of the gut microbiome community in murine models. In humans, vitamin D deficiency, accompanied by vitamin D receptor gene mutations, also contributes to changes in the gut microbiome. Moreover, gut microbiota status influences vitamin D distribution and metabolism. Alterations of the gut microbiota have also been studied in relation to radiotherapy. Some species of gut microbiota are associated with radiation resistance, while radiation can in turn influence the gut microbiota composition, where marked changes are frequently seen in <italic>Bifidobacterium</italic>, <italic>Clostridium</italic>, and <italic>Bacteroides spp</italic>. Radiotherapy affects vitamin D metabolism and distribution in the body, which in turn affects radiotherapy outcomes; there are vitamin D receptor polymorphisms having differential sensitivity to radiation.
<fig id="Fig4"><label>Fig. 4</label><caption><p>A triangle of the relationships among vitamin D, gut microbiota, and radiation-induced resistance</p></caption><graphic xlink:href="13046_2019_1499_Fig4_HTML" id="MO4"></graphic></fig></p><p id="Par15">The interactions among vitamin D, the gut microbiota, and radiotherapy outcomes are important for understanding radiation resistance. Substantial progress has been made in our understanding of these interactions at the molecular level, which could help to guide strategies aimed at overcoming radiation resistance in radiotherapy patients. Nevertheless, many questions remain, as follows. (i) How and to what extent do distinct molecular pathways lead to a pathological imbalance in the “love-hate triangle”?; (ii) Does an unstable gut microbiome lead to progressive dysregulation of vitamin D metabolism beyond a critical threshold for radiotherapy-induced radiation resistance?; (iii) What other dietary factors and microbiome metabolites are associated with host responses to radiotherapy, and through what molecular receptors and signaling pathways do they interact with vitamin D?; and (iv) Although gut microbiota transplantation has been documented in numerous studies, with encouraging outcomes, their clinical applications are limited. Could such transplantations serve as a novel intervention in radiation resistance?</p><p id="Par16">These questions are of great importance, given the fundamental challenges that remain with respect to overcoming radiation resistance and improving the quality of life of cancer patients. Obtaining answers to these questions will allow us to better understand the interactions among vitamin D, the gut microbiota, and radiotherapy outcomes, and could guide the development of new interventions to restore homeostasis in both the intestinal barrier and the microbiome.</p></sec></sec><sec id="Sec8"><title>Conclusion</title><p id="Par17">In conclusion, vitamin D and gut microbiota are key factors in shaping the radiation-induced resistance, and therefore, their impact on quality of patients’ life and cancer recurrence. However, the challenge now is to fully decipher the molecular mechanisms that link the vitamin D, gut microbiota, radiation resistance in a network of communication that impacts radiotherapy outcomes, to eventually translate these findings to the clinical prevention and control of radiation-induced resistance. Additional studies including measuring novel vitamin D metabolites by gut microbiota and utilizing randomized controlled trial to determine the impact of interaction of vitamin D and gut microbiota on benefit clinical radiotherapy outcomes in patients with cancer are warranted.</p></sec></body><back><fn-group><fn><p><bold>Publisher’s Note</bold></p><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn></fn-group><ack><p>N/A</p></ack><notes notes-type="author-contribution"><title>Authors’ contributions</title><p>PK Z conceived and designed the study; J X performed literature reviewing; RX H analyzed the data and performed the statistical analysis. RX H drafted the initial manuscript. PK Z critically reviewed and revised the manuscript. All authors read and approved the final Manuscript.</p></notes><notes notes-type="funding-information"><title>Funding</title><p>This study was supported by the National Natural Science Foundation of China (Grant No. U1803124, 31370843, 31500681), and the Natural Science Foundation of Hunan Province (Grant No. 2019JJ40396), and the Fundamental Research Funds for the Central Universities of Central South University (Grant Nos.2019zzts748, 2019zzts1011).</p></notes><notes notes-type="data-availability"><title>Availability of data and materials</title><p>Data sharing not applicable to this article as no datasets were generated or analysed during the current study.</p></notes><notes><title>Ethics approval and consent to participate</title><p id="Par18">N/A</p></notes><notes><title>Consent for publication</title><p id="Par19">N/A</p></notes><notes notes-type="COI-statement"><title>Competing interests</title><p id="Par20">The authors declare that they have no competing interests.</p></notes><ref-list id="Bib1"><title>References</title><ref id="CR1"><label>1.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lin</surname><given-names>L</given-names></name><name><surname>Yan</surname><given-names>L</given-names></name><name><surname>Liu</surname><given-names>Y</given-names></name><name><surname>Yuan</surname><given-names>F</given-names></name><name><surname>Li</surname><given-names>H</given-names></name><name><surname>Ni</surname><given-names>J</given-names></name></person-group><article-title>Incidence and death in 29 cancer groups in 2017 and trend analysis from 1990 to 2017 from the global burden of disease study</article-title><source>J Hematol Oncol</source><year>2019</year><volume>12</volume><issue>1</issue><fpage>96</fpage><pub-id pub-id-type="doi">10.1186/s13045-019-0783-9</pub-id><pub-id pub-id-type="pmid">31511035</pub-id></element-citation></ref><ref id="CR2"><label>2.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ferlay</surname><given-names>J</given-names></name><name><surname>Colombet</surname><given-names>M</given-names></name><name><surname>Soerjomataram</surname><given-names>I</given-names></name><name><surname>Mathers</surname><given-names>C</given-names></name><name><surname>Parkin</surname><given-names>DM</given-names></name><name><surname>Pineros</surname><given-names>M</given-names></name><name><surname>Znaor</surname><given-names>A</given-names></name><name><surname>Bray</surname><given-names>F</given-names></name></person-group><article-title>Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods</article-title><source>Int J Cancer</source><year>2019</year><volume>144</volume><issue>8</issue><fpage>1941</fpage><lpage>1953</lpage><pub-id pub-id-type="doi">10.1002/ijc.31937</pub-id><pub-id pub-id-type="pmid">30350310</pub-id></element-citation></ref><ref id="CR3"><label>3.</label><mixed-citation publication-type="other">Veness MJ, Delishaj D, Barnes EA, Bezugly A, Rembielak A. 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