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Review
. 2021 Jul 8;13(14):3431.
doi: 10.3390/cancers13143431.

Micro- and Mycobiota Dysbiosis in Pancreatic Ductal Adenocarcinoma Development

Ruben Bellotti  1 , Cornelia Speth  2 , Timon E Adolph  3 , Cornelia Lass-Flörl  2 , Maria Effenberger  3 , Dietmar Öfner  1 , Manuel Maglione  1
Affiliations
Review

Micro- and Mycobiota Dysbiosis in Pancreatic Ductal Adenocarcinoma Development

Ruben Bellotti et al. Cancers (Basel). .

Abstract

Background: Dysbiosis of the intestinal flora has emerged as an oncogenic contributor in different malignancies. Recent findings suggest a crucial tumor-promoting role of micro- and mycobiome alterations also in the development of pancreatic ductal adenocarcinoma (PDAC).

Methods: To summarize the current knowledge about this topic, a systematic literature search of articles published until October 2020 was performed in MEDLINE (PubMed).

Results: An increasing number of publications describe associations between bacterial and fungal species and PDAC development. Despite the high inter-individual variability of the commensal flora, some studies identify specific microbial signatures in PDAC patients, including oral commensals like Porphyromonas gingivalis and Fusobacterium nucleatum or Gram-negative bacteria like Proteobacteria. The role of Helicobacter spp. remains unclear. Recent isolation of Malassezia globosa from PDAC tissue suggest also the mycobiota as a crucial player of tumorigenesis. Based on described molecular mechanisms and interactions between the pancreatic tissue and the immune system this review proposes a model of how the micro- and the mycobial dysbiosis could contribute to tumorigenesis in PDAC.

Conclusions: The presence of micro- and mycobial dysbiosis in pancreatic tumor tissue opens a fascinating perspective on PDAC oncogenesis. Further studies will pave the way for novel tumor markers and treatment strategies.

Keywords: Malassezia; Proteobacteria; immunosuppression; inflammation; microbiome; mycobiome; pancreatic cancer; tumor initiation; tumor progression.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Proposed model of microbial dysbiosis driven pancreatic carcinogenesis. Phase 1: The tumor induction in the case of flora dysbiosis is related to the production of different substances that can be responsible for point mutations of genes like KRAS and TP53 of pancreatic ductal cells (e.g., polyamines produced by H. pylori and L. reuteri, or the enzyme peptidyl-arginine-deaminase of P. gingivalis). Phase 2: Tumor progression after the proliferation of the first cell-clone is sustained by bacterial-induced inflammation. Dysbiosis of the gut flora and alterations of the intestinal wall permeability originate from diet-disbalance and finally facilitate the migration of microorganisms into the pancreas. In particular, the translocation of Gram-negative bacteria elicits an inflammatory response. This one occurs when PMNs recognize bacterial LPS via TLR4 with consequent production of ROS. In this way, the establishment of an oxidative stress disbalance sustains the carcinogenic process. Phase 3: Intrapancreatic mechanisms of receptor-related molecular feedback lead for a second time to a switch of the immune response towards a tolerogenic phenotype. In particular, the activation of TLR4 expressed by DCs and M2-polarized TAM induces Th2-deviated CD4+ cells. However, it is still unclear if this receptor function of TLR4 depends on binding of either bacterial LPS or other uncharacterized tumoral products (marked with “?” in the picture) [47,48]. Furthermore, the activation of TLR9, an essential receptor for the recognition of CpG bacterial-DNA expressed on PSCs, stimulates the production of fibrous stroma and the expression of CCL11, a mediator with pro-tumorigenic effects on pancreatic ductal cells. TLR9 activation also leads to the PSC-dependent recruitment of Treg and MDSCs in the TME [49]. Abbreviations: DC: dendritic cell; MDSC: myeloid-derived suppressor cell; PMN: polymorphonuclear cells; PSCs: pancreatic stellate cells; ROS: radical oxygen species; TAM (M2): tumor-associated macrophages with M2 polarization; Th2: T-helper type 2 cells; Treg: T-regulatory cells. (Picture created in BioRender.com, https://biorender.com, accessed on 23 April 2021).
Figure 2
Figure 2
Proposed model of the role of Malassezia spp. in pancreatic tumor progression. The relation between Malassezia and pancreatic tumor progression is linked to the action of both cellular and molecular effectors, which lead to an intratumoral immune shaping. (1) Dendritic-cells (DCs): the synchronous recognition of fungal antigens like 1,3- and 1,6-β glucan by DCs lead to the production of GM-CSF [89], with consequent cell-expansion and release of indoleamine 2,3-dioxygenase (IDO), IL-10, and TGF-β. These mediators favor the activation of Treg, which inhibit T-cells cytotoxicity (CD8+) and stimulate a switch of tumor-associated macrophages (TAM) towards an M2-phenotype [90]. On the other hand, IL-10 and TGF-β, together with VEGF produced by the TAMs, stimulate the intratumoral angiogenesis. Thanks to the expansion of DCs, more Dectin-1 can bind Galectin-9, a lectin expressed on tumor cell membrane, and contribute to the M2-shift of the TAM [91]. Moreover, Dectin-1 can bind Annexin-1 on dying tumoral cells, leading to NF-kB inactivation [92,93]. (2) Complement system: the recognition of Malassezia through MBL activates the complement cascade, leading to formation of active C3 and C5 convertases. Among the different complement components, C3a and C5a both lead to tumor cell proliferation by binding their specific receptors expressed on PDAC cells. Furthermore, the signaling of C3aR increases the epithelial–mesenchymal transition (EMT), promoting the metastatic process. C5a acts in an immunosuppressive way by inducing apoptosis of CD8+ cytotoxic cells, attracting MDSC into the tumor, and participating in the shift of the macrophages towards an M2-phenotype [87]. Of note, the fact that TAMs can induce the expression of CD59 on PDAC cells limits the antitumoral activity of the MAC. Abbreviations: C3-conv: C3-convertase; C5-conv: C5-convertase; CD8+: cytotoxic CD8+ T-cells; DC: dendritic cell; EMT: epithelial-mesenchymal transition; IDO: indoleamine 2,3-dioxygenase; MAC: membrane attack complex of the complement system; MBL: mannose binding lectin; MDSC: myeloid-derived suppressor cell; TAM: tumor associated macrophages M2 polarized; Treg: T-helper regulatory cell; VEGF: vascular endothelial growth factor. (Picture created in BioRender.com, https://biorender.com, accessed on 23 April 2021).
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