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Biological Interfaces in Gastrointestinal Cancer
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Biological Interfaces in Gastrointestinal Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 107998

Special Issue Editors

Dr. Andre Lechel

E-Mail Website
Guest Editor
Department of Internal Medicine I, Ulm University, 89081 Ulm, Germany
Interests: liver carcinogenesis; tumor differentiation; chronic liver disease; liver stem cells; tumor stem cells; p53-signalling; aging; telomeres
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Reinhold Schirmbeck

E-Mail Website
Co-Guest Editor
Department of Internal Medicine I, Ulm University, 89081 Ulm, Germany
Interests: CD8 T cells; genetic vaccines; mouse models of chronic HBV infection; development of novel immune therapies against tumors and autoimmune type 1 diabetes; the aging immune system
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The focus of this Special Issue is on the role of communication in gastrointestinal cancers, involving cell-to-cell communication, like communication between the microenvironment or the immune system and the tumor cell, as well as communication on the molecular level, like Wnt, NF-kB, and Mtor, which play major roles in signal transduction.

Gastrointestinal cancer, like colorectal cancer, pancreatic cancer, and hepatocellular cancer, belong to the most common causes of cancer mortality and therfore present a major health problem. Gastrointestinal cancers are characterized by their huge heterogeneity, even if many mutations are present in several tumor entities.  

A detailed molecular tumor analysis on biological interfaces is increasingly fundamental in choosing the most appropriate anti-cancer therapy for patients and opening new doors for the development of precision medicine. Interdisciplinary teamwork with colleagues in pathology, bioinformatics, immunology, molecular biology, and other disciplines will help oncologists, integrating data and expertise from the work of professionals involved in prevention, early-diagnosis, and basic and translational cancer research.

In this Special Issue, we invite your contributions, either in the form of original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “Biological Interfaces in Gastrointestinal Cancer”.

Dr. Andre Lechel
Prof. Dr. Reinhold Schirmbeck
Guest Editors

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Keywords

  • Liver cancer
  • Pancreatic cancer
  • Intestinal cancer
  • Gastric cancer
  • Tissue inflammation
  • Microenvironment
  • Innate and adaptive immune responses
  • Checkpoint inhibitors
  • Immunotherapy
  • Precision medicine
  • Model systems (e.g., transgenic mouse models, organoid culture).

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Published Papers (25 papers)

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Research

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18 pages, 3136 KiB  
Article
Establishment and Characterization of Immortalized Miniature Pig Pancreatic Cell Lines Expressing Oncogenic K-RasG12D
by Hae-Jun Yang, Bong-Seok Song, Bo-Woong Sim, Yena Jung, Unbin Chae, Dong Gil Lee, Jae-Jin Cha, Seo-Jong Baek, Kyung Seob Lim, Won Seok Choi, Hwal-Yong Lee, Hee-Chang Son, Sung-Hyun Park, Kang-Jin Jeong, Philyong Kang, Seung Ho Baek, Bon-Sang Koo, Han-Na Kim, Yeung Bae Jin, Young-Ho Park, Young-Kug Choo and Sun-Uk Kimadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2020, 21(22), 8820; https://doi.org/10.3390/ijms21228820 - 21 Nov 2020
Cited by 1 | Viewed by 3184
Abstract
In recent decades, many studies on the treatment and prevention of pancreatic cancer have been conducted. However, pancreatic cancer remains incurable, with a high mortality rate. Although mouse models have been widely used for preclinical pancreatic cancer research, these models have many differences [...] Read more.
In recent decades, many studies on the treatment and prevention of pancreatic cancer have been conducted. However, pancreatic cancer remains incurable, with a high mortality rate. Although mouse models have been widely used for preclinical pancreatic cancer research, these models have many differences from humans. Therefore, large animals may be more useful for the investigation of pancreatic cancer. Pigs have recently emerged as a new model of pancreatic cancer due to their similarities to humans, but no pig pancreatic cancer cell lines have been established for use in drug screening or analysis of tumor biology. Here, we established and characterized an immortalized miniature pig pancreatic cell line derived from primary pancreatic cells and pancreatic cancer-like cells expressing K-rasG12D regulated by the human PTF1A promoter. Using this immortalized cell line, we analyzed the gene expression and phenotypes associated with cancer cell characteristics. Notably, we found that acinar-to-ductal transition was caused by K-rasG12D in the cell line constructed from acinar cells. This may constitute a good research model for the analysis of acinar-to-ductal metaplasia in human pancreatic cancer. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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22 pages, 3507 KiB  
Article
Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells
by Sonia Alcalá, Víctor Mayoral-Varo, Laura Ruiz-Cañas, Juan Carlos López-Gil, Christopher Heeschen, Jorge Martín-Pérez and Bruno Sainz, Jr.
Int. J. Mol. Sci. 2020, 21(20), 7437; https://doi.org/10.3390/ijms21207437 - 9 Oct 2020
Cited by 20 | Viewed by 3074 | Correction
Abstract
The proto-oncogene nonreceptor tyrosine-protein kinase SRC is a member of the SRC family of tyrosine kinases (SFKs), and its activation and overexpression have been shown to play a protumorigenic role in multiple solid cancers, including pancreatic ductal adenocarcinoma (PDAC). PDAC is currently the [...] Read more.
The proto-oncogene nonreceptor tyrosine-protein kinase SRC is a member of the SRC family of tyrosine kinases (SFKs), and its activation and overexpression have been shown to play a protumorigenic role in multiple solid cancers, including pancreatic ductal adenocarcinoma (PDAC). PDAC is currently the seventh-leading cause of cancer-related death worldwide, and, by 2030, it is predicted to become the second-leading cause of cancer-related death in the United States. PDAC is characterized by its high lethality (5-year survival of rate of <10%), invasiveness, and chemoresistance, all of which have been shown to be due to the presence of pancreatic cancer stem cells (PaCSCs) within the tumor. Due to the demonstrated overexpression of SRC in PDAC, we set out to determine if SRC kinases are important for PaCSC biology using pharmacological inhibitors of SRC kinases (dasatinib or PP2). Treatment of primary PDAC cultures established from patient-derived xenografts with dasatinib or PP2 reduced the clonogenic, self-renewal, and tumor-initiating capacity of PaCSCs, which we attribute to the downregulation of key signaling factors such as p-FAK, p-ERK1-2, and p-AKT. Therefore, this study not only validates that SRC kinases are relevant and biologically important for PaCSCs but also suggests that inhibitors of SRC kinases may represent a possible future treatment option for PDAC patients, although further studies are still needed. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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15 pages, 1858 KiB  
Article
Transcriptome and Gene Fusion Analysis of Synchronous Lesions Reveals lncMRPS31P5 as a Novel Transcript Involved in Colorectal Cancer
by Anna Panza, Stefano Castellana, Giuseppe Biscaglia, Ada Piepoli, Luca Parca, Annamaria Gentile, Anna Latiano, Tommaso Mazza, Francesco Perri, Angelo Andriulli and Orazio Palmieri
Int. J. Mol. Sci. 2020, 21(19), 7120; https://doi.org/10.3390/ijms21197120 - 27 Sep 2020
Cited by 3 | Viewed by 2816
Abstract
Fusion genes and epigenetic regulators (i.e., miRNAs and long non-coding RNAs) constitute essential pieces of the puzzle of the tumor genomic landscape, in particular in mechanisms behind the adenoma-to-carcinoma progression of colorectal cancer (CRC). In this work, we aimed to identify molecular signatures [...] Read more.
Fusion genes and epigenetic regulators (i.e., miRNAs and long non-coding RNAs) constitute essential pieces of the puzzle of the tumor genomic landscape, in particular in mechanisms behind the adenoma-to-carcinoma progression of colorectal cancer (CRC). In this work, we aimed to identify molecular signatures of the different steps of sporadic CRC development in eleven patients, of which synchronous samples of adenomas, tumors, and normal tissues were analyzed by RNA-Seq. At a functional level, tumors and adenomas were all characterized by increased activity of the cell cycle, cell development, cell growth, and biological proliferation functions. In contrast, organic survival and apoptosis-related functions were inhibited both in tumors and adenomas at different levels. At a molecular level, we found that three individuals shared a tumor-specific fusion named MRPS31-SUGT1, generated through an intra-chromosomal translocation on chromosome 13, whose sequence resulted in being 100% identical to the long non-coding RNA (lncRNA) MRPS31P5. Our analyses suggest that MRPS31P5 could take part to a competitive endogenous (ce)RNA network by acting as a miRNA sponge or/and as an interactor of other mRNAs, and thus it may be an important gene expression regulatory factor and could be used as a potential biomarker for the detection of early CRC events. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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16 pages, 2512 KiB  
Article
Downregulation of ORP3 Correlates with Reduced Survival of Colon Cancer Patients with Advanced Nodal Metastasis and of Female Patients with Grade 3 Colon Cancer
by Pengfei Xu, Julia Richter, Annette Blatz, Fabian Gärtner, Roland Alberts, Anca Azoitei, Wycliffe Arika Makori, Sabine Meessen, Uwe Knippschild and Cagatay Günes
Int. J. Mol. Sci. 2020, 21(16), 5894; https://doi.org/10.3390/ijms21165894 - 16 Aug 2020
Cited by 10 | Viewed by 3049
Abstract
Genome instability is an essential hallmark in tumor development, including colorectal cancer. We have recently identified the oxysterol binding protein-related protein 3 (ORP3), also known as oxysterol binding protein-like 3 (OSBPL3), as a novel ploidy-control gene, whose knock-out leads to aneuploidy induction and [...] Read more.
Genome instability is an essential hallmark in tumor development, including colorectal cancer. We have recently identified the oxysterol binding protein-related protein 3 (ORP3), also known as oxysterol binding protein-like 3 (OSBPL3), as a novel ploidy-control gene, whose knock-out leads to aneuploidy induction and promotes tumor formation, indicating that ORP3 is a bona fide tumor suppressor protein. Here we analyzed expression of ORP3 in a cohort (n = 206) of colon cancer patients in relation to patient survival. We show that low ORP3 mRNA levels correlate with reduced survival of patients with advanced nodal metastasis (N2). While patient survival does not associate with grading when the whole cohort is evaluated, importantly, low ORP3 mRNA levels associate with worse survival of female patients with grade 3 colon cancer. Similarly, low ORP3 mRNA levels associate with worse survival of grade 3 colon cancer patients 70 years of age and younger while low ORP3 mRNA levels seem to be beneficial for colon cancer patients with a T2 tumor size. Together, the data show that ORP3 expression is downregulated during colon cancer progression, which correlates with reduced patient survival. Thus, ORP3 mRNA levels may be a prognostic marker for better stratification of colon cancer patients. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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14 pages, 3679 KiB  
Article
Comprehensive Analysis of Expression, Clinicopathological Association and Potential Prognostic Significance of RABs in Pancreatic Cancer
by Shashi Anand, Mohammad Aslam Khan, Moh’d Khushman, Santanu Dasgupta, Seema Singh and Ajay Pratap Singh
Int. J. Mol. Sci. 2020, 21(15), 5580; https://doi.org/10.3390/ijms21155580 - 4 Aug 2020
Cited by 14 | Viewed by 3888
Abstract
RAB proteins (RABs) represent the largest subfamily of Ras-like small GTPases that regulate a wide variety of endosomal membrane transport pathways. Their aberrant expression has been demonstrated in various malignancies and implicated in pathogenesis. Using The Cancer Genome Atlas (TCGA) database, we analyzed [...] Read more.
RAB proteins (RABs) represent the largest subfamily of Ras-like small GTPases that regulate a wide variety of endosomal membrane transport pathways. Their aberrant expression has been demonstrated in various malignancies and implicated in pathogenesis. Using The Cancer Genome Atlas (TCGA) database, we analyzed the differential expression and clinicopathological association of RAB genes in pancreatic ductal adenocarcinoma (PDAC). Of the 62 RAB genes analyzed, five (RAB3A, RAB26, RAB25, RAB21, and RAB22A) exhibited statistically significant upregulation, while five (RAB6B, RAB8B, RABL2A, RABL2B, and RAB32) were downregulated in PDAC as compared to the normal pancreas. Racially disparate expression was also reported for RAB3A, RAB25, and RAB26. However, no clear trend of altered expression was observed with increasing stage and grade, age, and gender of the patients. PDAC from occasional drinkers had significantly higher expression of RAB21 compared to daily or weekly drinkers, whereas RAB25 expression was significantly higher in social drinkers, compared to occasional ones. The expression of RABL2A was significantly reduced in PDAC from diabetic patients, whereas RAB26 was significantly lower in pancreatitis patients. More importantly, a significant association of high expression of RAB21, RAB22A, and RAB25, and low expression of RAB6B, RABL2A, and RABL2B was observed with poorer survival of PC patients. Together, our study suggests potential diagnostic and prognostic significance of RABs in PDAC, warranting further investigations to define their functional and mechanistic significance. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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13 pages, 2289 KiB  
Article
Increased Oxidative Phosphorylation Is Required for Stemness Maintenance in Liver Cancer Stem Cells from Hepatocellular Carcinoma Cell Line HCCLM3 Cells
by Ge Liu, Qing Luo, Hong Li, Qiuping Liu, Yang Ju and Guanbin Song
Int. J. Mol. Sci. 2020, 21(15), 5276; https://doi.org/10.3390/ijms21155276 - 25 Jul 2020
Cited by 40 | Viewed by 4091
Abstract
Cancer stem cells (CSCs) are considered to be the main cause of tumor recurrence, metastasis, and an unfavorable prognosis. Energy metabolism is closely associated with cell stemness. However, how the stemness of liver cancer stem cells (LCSCs) is regulated by metabolic/oxidative stress remains [...] Read more.
Cancer stem cells (CSCs) are considered to be the main cause of tumor recurrence, metastasis, and an unfavorable prognosis. Energy metabolism is closely associated with cell stemness. However, how the stemness of liver cancer stem cells (LCSCs) is regulated by metabolic/oxidative stress remains poorly understood. In this study, we compare the metabolic differences between LCSCs and the hepatocellular carcinoma cell line HCCLM3, and explore the relationship between metabolism and LCSC stemness. We found that LCSCs from the hepatocellular carcinoma cell HCCLM3 exhibited more robust glucose metabolism than HCCLM3, including glycolysis, oxidative phosphorylation (OXPHOS), and pyruvate produced by glycolysis entering mitochondria for OXPHOS. Moreover, 2-deoxy-D-glucose (2-DG) enhanced the LCSC stemness by upregulating OXPHOS. In contrast, Mdivi-1 reduced the levels of OXPHOS and weakened the stemness by inhibiting mitochondrial fission. Together, our findings clarify the relationship between energy metabolism and LCSC stemness and may provide theoretical guidance and potential therapeutic approaches for liver cancer. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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18 pages, 3875 KiB  
Article
Expression of HTRA Genes and Its Association with Microsatellite Instability and Survival of Patients with Colorectal Cancer
by Dorota Zurawa-Janicka, Jarek Kobiela, Tomasz Slebioda, Rafal Peksa, Marcin Stanislawowski, Piotr Mieczyslaw Wierzbicki, Tomasz Wenta, Barbara Lipinska, Zbigniew Kmiec, Wojciech Biernat, Andrzej Jacek Lachinski and Zbigniew Sledzinski
Int. J. Mol. Sci. 2020, 21(11), 3947; https://doi.org/10.3390/ijms21113947 - 31 May 2020
Cited by 8 | Viewed by 2968
Abstract
HtrA proteases regulate cellular homeostasis and cell death. Their dysfunctions have been correlated with oncogenesis and response to therapeutic treatment. We investigated the relation between HtrA1-3 expression and clinicopathological, and survival data, as well as the microsatellite status of tumors. Sixty-five colorectal cancer [...] Read more.
HtrA proteases regulate cellular homeostasis and cell death. Their dysfunctions have been correlated with oncogenesis and response to therapeutic treatment. We investigated the relation between HtrA1-3 expression and clinicopathological, and survival data, as well as the microsatellite status of tumors. Sixty-five colorectal cancer patients were included in the study. The expression of HTRA1-3 was estimated at the mRNA and protein levels by quantitative PCR and immunoblotting. Microsatellite status was determined by high-resolution-melting PCR. We found that the HTRA1 mRNA level was higher in colorectal cancer tissue as compared to the unchanged mucosa, specifically in primary lesions of metastasizing cancer. The levels of HtrA1 and HtrA2 proteins were reduced in tumor tissue when compared to unchanged mucosa, specifically in primary lesions of metastasizing disease. Moreover, a decrease in HTRA1 and HTRA2 transcripts’ levels in cancers with a high level of microsatellite instability compared to microsatellite stable ones has been observed. A low level of HtrA1 or/and HtrA2 in cancer tissue correlated with poorer patient survival. The expression of HTRA1 and HTRA2 changes during colorectal carcinogenesis and microsatellite instability may be, at least partially, associated with these changes. The alterations in the HTRA1/2 genes’ expression are connected with metastatic potential of colorectal cancer and may affect patient survival. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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16 pages, 7800 KiB  
Article
Aberrant Expression of RAD52, Its Prognostic Impact in Rectal Cancer and Association with Poor Survival of Patients
by Vincent Ho, Liping Chung, Amandeep Singh, Vivienne Lea, Askar Abubakar, Stephanie H. Lim, Wei Chua, Weng Ng, Mark Lee, Tara L. Roberts, Paul de Souza and Cheok Soon Lee
Int. J. Mol. Sci. 2020, 21(5), 1768; https://doi.org/10.3390/ijms21051768 - 4 Mar 2020
Cited by 11 | Viewed by 3304
Abstract
The DNA damage response enables cells to survive and maintain genome integrity. RAD52 is a DNA-binding protein involved in the homologous recombination in DNA repair, and is important for the maintenance of tumour genome integrity. We investigated possible correlations between RAD52 expression and [...] Read more.
The DNA damage response enables cells to survive and maintain genome integrity. RAD52 is a DNA-binding protein involved in the homologous recombination in DNA repair, and is important for the maintenance of tumour genome integrity. We investigated possible correlations between RAD52 expression and cancer survival and response to preoperative radiotherapy. RAD52 expression was examined in tumour samples from 179 patients who underwent surgery for rectal cancer, including a sub-cohort of 40 patients who were treated with neoadjuvant therapy. A high score for RAD52 expression in the tumour centre was significantly associated with worse disease-free survival (DFS; p = 0.045). In contrast, reduced RAD52 expression in tumour centre samples from patients treated with neoadjuvant therapy (n = 40) significantly correlated with poor DFS (p = 0.025) and overall survival (OS; p = 0.048). Our results suggested that RAD52 may have clinical value as a prognostic marker of tumour response to neoadjuvant radiation and both disease-free status and overall survival in patients with rectal cancer. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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Review

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15 pages, 349 KiB  
Review
Iron at the Interface of Hepatocellular Carcinoma
by Rossana Paganoni, André Lechel and Maja Vujic Spasic
Int. J. Mol. Sci. 2021, 22(8), 4097; https://doi.org/10.3390/ijms22084097 - 15 Apr 2021
Cited by 34 | Viewed by 3816
Abstract
Cancer incidence and mortality are rapidly growing, with liver cancer being the sixth most diagnosed cancer worldwide and the third leading cause of cancer death in 2020. A number of risk factors have been identified that trigger the progression to hepatocellular carcinoma. In [...] Read more.
Cancer incidence and mortality are rapidly growing, with liver cancer being the sixth most diagnosed cancer worldwide and the third leading cause of cancer death in 2020. A number of risk factors have been identified that trigger the progression to hepatocellular carcinoma. In this review, we focus on iron as a potential risk factor for liver carcinogenesis. Molecules involved in the regulation of iron metabolism are often upregulated in cancer cells, in order to provide a supply of this essential trace element for all stages of tumor development, survival, proliferation, and metastasis. Thus, cellular and systemic iron levels must be tightly regulated to prevent or delay liver cancer progression. Disorders associated with dysregulated iron metabolism are characterized with increased susceptibility to hepatocellular carcinoma. This review discusses the association of iron with metabolic disorders such as hereditary hemochromatosis, non-alcoholic fatty liver disease, obesity, and type 2 diabetes, in the background of hepatocellular carcinoma. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
20 pages, 682 KiB  
Review
Possible Roles of Interleukin-4 and -13 and Their Receptors in Gastric and Colon Cancer
by Xujun Song, Benno Traub, Jingwei Shi and Marko Kornmann
Int. J. Mol. Sci. 2021, 22(2), 727; https://doi.org/10.3390/ijms22020727 - 13 Jan 2021
Cited by 48 | Viewed by 7553
Abstract
Interleukin (IL)-4 and -13 are structurally and functionally related cytokines sharing common receptor subunits. They regulate immune responses and, moreover, are involved in the pathogenesis of a variety of human neoplasms. Three different receptors have been described for IL-4, but only IL-4 receptor [...] Read more.
Interleukin (IL)-4 and -13 are structurally and functionally related cytokines sharing common receptor subunits. They regulate immune responses and, moreover, are involved in the pathogenesis of a variety of human neoplasms. Three different receptors have been described for IL-4, but only IL-4 receptor type II (IL-4Rα/IL-13Rα1) is expressed in solid tumors. While IL-13 can also bind to three different receptors, IL-13 receptor type I (IL-4Rα/IL-13Rα1/IL-13Rα2) and type II (IL-4Rα/IL-13Rα1) are expressed in solid tumors. After receptor binding, IL-4 and IL-13 can mediate tumor cell proliferation, survival, and metastasis in gastric or colon cancer. This review summarizes the results about the role of IL-4/IL-13 and their receptors in gastric and colon cancer. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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23 pages, 2013 KiB  
Review
Roles of Lysyl Oxidase Family Members in the Tumor Microenvironment and Progression of Liver Cancer
by Hung-Yu Lin, Chia-Jung Li, Ya-Ling Yang, Ying-Hsien Huang, Ya-Tze Hsiau and Pei-Yi Chu
Int. J. Mol. Sci. 2020, 21(24), 9751; https://doi.org/10.3390/ijms21249751 - 21 Dec 2020
Cited by 26 | Viewed by 4079
Abstract
The lysyl oxidase (LOX) family members are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like l-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a [...] Read more.
The lysyl oxidase (LOX) family members are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like l-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a key role in the angiogenesis surrounding tumors, whereby a corrupt tumor microenvironment (TME) takes shape. Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), ranked as the seventh most common cancer globally, with limited therapeutic options for advanced stages. In recent years, a growing body of evidence has revealed the key roles of LOX family members in the pathogenesis of liver cancer and the shaping of TME, indicating their notable potential as therapeutic targets. We herein review the clinical value and novel biological roles of LOX family members in tumor progression and the TME of liver cancers. In addition, we highlight recent insights into their mechanisms and their potential involvement in the development of target therapy for liver cancer. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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24 pages, 1438 KiB  
Review
Microbe-Driven Genotoxicity in Gastrointestinal Carcinogenesis
by Kimberly Hartl and Michael Sigal
Int. J. Mol. Sci. 2020, 21(20), 7439; https://doi.org/10.3390/ijms21207439 - 9 Oct 2020
Cited by 13 | Viewed by 3968
Abstract
The intestinal epithelium serves as a barrier to discriminate the outside from the inside and is in constant exchange with the luminal contents, including nutrients and the microbiota. Pathogens have evolved mechanisms to overcome the multiple ways of defense in the mucosa, while [...] Read more.
The intestinal epithelium serves as a barrier to discriminate the outside from the inside and is in constant exchange with the luminal contents, including nutrients and the microbiota. Pathogens have evolved mechanisms to overcome the multiple ways of defense in the mucosa, while several members of the microbiota can exhibit pathogenic features once the healthy barrier integrity of the epithelium is disrupted. This not only leads to symptoms accompanying the acute infection but may also contribute to long-term injuries such as genomic instability, which is linked to mutations and cancer. While for Helicobacter pylori a link between infection and cancer is well established, many other bacteria and their virulence factors have only recently been linked to gastrointestinal malignancies through epidemiological as well as mechanistic studies. This review will focus on those pathogens and members of the microbiota that have been linked to genotoxicity in the context of gastric or colorectal cancer. We will address the mechanisms by which such bacteria establish contact with the gastrointestinal epithelium—either via an existing breach in the barrier or via their own virulence factors as well as the mechanisms by which they interfere with host genomic integrity. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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28 pages, 2159 KiB  
Review
The Role of Micro-RNAs and Circulating Tumor Markers as Predictors of Response to Neoadjuvant Therapy in Locally Advanced Rectal Cancer
by Fatima Domenica Elisa De Palma, Gaetano Luglio, Francesca Paola Tropeano, Gianluca Pagano, Maria D’Armiento, Guido Kroemer, Maria Chiara Maiuri and Giovanni Domenico De Palma
Int. J. Mol. Sci. 2020, 21(19), 7040; https://doi.org/10.3390/ijms21197040 - 24 Sep 2020
Cited by 29 | Viewed by 3735
Abstract
The response to neoadjuvant chemoradiation (nCRT) is a critical step in the management of locally advanced rectal cancer (LARC) patients. Only a minority of LARC patients responds completely to neoadjuvant treatments, thus avoiding invasive radical surgical resection. Moreover, toxic side effects can adversely [...] Read more.
The response to neoadjuvant chemoradiation (nCRT) is a critical step in the management of locally advanced rectal cancer (LARC) patients. Only a minority of LARC patients responds completely to neoadjuvant treatments, thus avoiding invasive radical surgical resection. Moreover, toxic side effects can adversely affect patients’ survival. The difficulty in separating in advances responder from non-responder patients affected by LARC highlights the need for valid biomarkers that guide clinical decision-making. In this context, microRNAs (miRNAs) seem to be promising candidates for predicting LARC prognosis and/or therapy response, particularly due to their stability, facile detection, and disease-specific expression in human tissues, blood, serum, or urine. Although a considerable number of studies involving potential miRNA predictors to nCRT have been conducted over the years, to date, the identification of the perfect miRNA signatures or single miRNA, as well as their use in the clinical practice, is still representing a challenge for the management of LARC patients. In this review, we will first introduce LARC and its difficult management. Then, we will trace the scientific history and the key obstacles for the identification of specific miRNAs that predict responsiveness to nCRT. There is a high potential to identify non-invasive biomarkers that circulate in the human bloodstream and that might indicate the LARC patients who benefit from the watch-and-wait approach. For this, we will critically evaluate recent advances dealing with cell-free nucleic acids including miRNAs and circulating tumor cells as prognostic or predictive biomarkers. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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17 pages, 1146 KiB  
Review
NASH, Fibrosis and Hepatocellular Carcinoma: Lipid Synthesis and Glutamine/Acetate Signaling
by Yoshiaki Sunami
Int. J. Mol. Sci. 2020, 21(18), 6799; https://doi.org/10.3390/ijms21186799 - 16 Sep 2020
Cited by 13 | Viewed by 5731
Abstract
Primary liver cancer is predicted to be the sixth most common cancer and the fourth leading cause of cancer mortality worldwide. Recent studies identified nonalcoholic fatty liver disease (NAFLD) as the underlying cause in 13–38.2% of patients with hepatocellular carcinoma unrelated to viral [...] Read more.
Primary liver cancer is predicted to be the sixth most common cancer and the fourth leading cause of cancer mortality worldwide. Recent studies identified nonalcoholic fatty liver disease (NAFLD) as the underlying cause in 13–38.2% of patients with hepatocellular carcinoma unrelated to viral hepatitis and alcohol abuse. NAFLD progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is characterized by dysregulation of lipid metabolism. In addition, lipid metabolism is effected not only in NAFLD, but also in a broad range of chronic liver diseases and tumor development. Cancer cells manipulate a variety of metabolic pathways, including lipid metabolism, in order to build up their own cellular components. Identifying tumor dependencies on lipid metabolism would provide options for novel targeting strategies. This review article summarizes the research evidence on metabolic reprogramming and focuses on lipid metabolism in NAFLD, NASH, fibrosis, and cancer. As alternative routes of acetyl-CoA production for fatty acid synthesis, topics on glutamine and acetate metabolism are included. Further, studies on small compound inhibitors targeting lipid metabolism are discussed. Understanding reprogramming strategies in liver diseases, as well as the visualization of the metabolism reprogramming networks, could uncover novel therapeutic options. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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20 pages, 964 KiB  
Review
Preventing Tumour Recurrence after Liver Transplantation: The Role of Machine Perfusion
by Yuri Boteon, Mauricio Alfredo Flores Carvalho, Rebecca Panconesi, Paolo Muiesan and Andrea Schlegel
Int. J. Mol. Sci. 2020, 21(16), 5791; https://doi.org/10.3390/ijms21165791 - 12 Aug 2020
Cited by 13 | Viewed by 4183
Abstract
Tumour recurrence is currently a hot topic in liver transplantation. The basic mechanisms are increasingly discussed, and, for example, recurrence of hepatocellular carcinoma is often described in pre-injured donor livers, which frequently suffer from significant ischemia/reperfusion injury. This review article highlights the underlying [...] Read more.
Tumour recurrence is currently a hot topic in liver transplantation. The basic mechanisms are increasingly discussed, and, for example, recurrence of hepatocellular carcinoma is often described in pre-injured donor livers, which frequently suffer from significant ischemia/reperfusion injury. This review article highlights the underlying mechanisms and describes the specific tissue milieu required to promote tumour recurrence after liver transplantation. We summarise the current literature in this field and show risk factors that contribute to a pro-tumour-recurrent environment. Finally, the potential role of new machine perfusion technology is discussed, including the most recent data, which demonstrate a protective effect of hypothermic oxygenated perfusion before liver transplantation. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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29 pages, 2723 KiB  
Review
DNA Mismatch Repair Gene Variants in Sporadic Solid Cancers
by Fabian Caja, Ludmila Vodickova, Jan Kral, Veronika Vymetalkova, Alessio Naccarati and Pavel Vodicka
Int. J. Mol. Sci. 2020, 21(15), 5561; https://doi.org/10.3390/ijms21155561 - 3 Aug 2020
Cited by 17 | Viewed by 4877
Abstract
The phenotypic effects of single nucleotide polymorphisms (SNPs) in the development of sporadic solid cancers are still scarce. The aim of this review was to summarise and analyse published data on the associations between SNPs in mismatch repair genes and various cancers. The [...] Read more.
The phenotypic effects of single nucleotide polymorphisms (SNPs) in the development of sporadic solid cancers are still scarce. The aim of this review was to summarise and analyse published data on the associations between SNPs in mismatch repair genes and various cancers. The mismatch repair system plays a unique role in the control of the genetic integrity and it is often inactivated (germline and somatic mutations and hypermethylation) in cancer patients. Here, we focused on germline variants in mismatch repair genes and found the outcomes rather controversial: some SNPs are sometimes ascribed as protective, while other studies reported their pathological effects. Regarding the complexity of cancer as one disease, we attempted to ascertain if particular polymorphisms exert the effect in the same direction in the development and treatment of different malignancies, although it is still not straightforward to conclude whether polymorphisms always play a clear positive role or a negative one. Most recent and robust genome-wide studies suggest that risk of cancer is modulated by variants in mismatch repair genes, for example in colorectal cancer. Our study shows that rs1800734 in MLH1 or rs2303428 in MSH2 may influence the development of different malignancies. The lack of functional studies on many DNA mismatch repair SNPs as well as their interactions are not explored yet. Notably, the concerted action of more variants in one individual may be protective or harmful. Further, complex interactions of DNA mismatch repair variations with both the environment and microenvironment in the cancer pathogenesis will deserve further attention. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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21 pages, 689 KiB  
Review
Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities
by Matteo Canale, Andrea Casadei-Gardini, Paola Ulivi, Maria Arechederra, Carmen Berasain, Pier-Luigi Lollini, Maite G. Fernández-Barrena and Matías A. Avila
Int. J. Mol. Sci. 2020, 21(15), 5500; https://doi.org/10.3390/ijms21155500 - 31 Jul 2020
Cited by 31 | Viewed by 5317
Abstract
Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer [...] Read more.
Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. Moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. In this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. In this review, we summarize the key epigenetic events involved in gastric cancer development. We conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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23 pages, 1843 KiB  
Review
Crosstalk between Tumor and Stromal Cells in Pancreatic Ductal Adenocarcinoma
by Nadine Sperb, Miltiadis Tsesmelis and Thomas Wirth
Int. J. Mol. Sci. 2020, 21(15), 5486; https://doi.org/10.3390/ijms21155486 - 31 Jul 2020
Cited by 69 | Viewed by 8562
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal cancer. The poor prognosis calls for a more detailed understanding of disease biology in order to pave the way for the development of effective therapies. Typically, the pancreatic tumor is composed of a minority of malignant [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal cancer. The poor prognosis calls for a more detailed understanding of disease biology in order to pave the way for the development of effective therapies. Typically, the pancreatic tumor is composed of a minority of malignant cells within an excessive tumor microenvironment (TME) consisting of extracellular matrix (ECM), fibroblasts, immune cells, and endothelial cells. Research conducted in recent years has particularly focused on cancer-associated fibroblasts (CAFs) which represent the most prominent cellular component of the desmoplastic stroma. Here, we review the complex crosstalk between CAFs, tumor cells, and other components of the TME, and illustrate how these interactions drive disease progression. We also discuss the emerging field of CAF heterogeneity, their tumor-supportive versus tumor-suppressive capacity, and the consequences for designing stroma-targeted therapies in the future. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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18 pages, 676 KiB  
Review
Molecular Targets, Pathways, and Therapeutic Implications for Hepatocellular Carcinoma
by Jun Gong, Jeremy Chuang, May Cho, Kyra Toomey, Andrew Hendifar and Daneng Li
Int. J. Mol. Sci. 2020, 21(15), 5232; https://doi.org/10.3390/ijms21155232 - 23 Jul 2020
Cited by 11 | Viewed by 3194
Abstract
Hepatocellular carcinoma (HCC) represents one of the leading causes of cancer mortality worldwide. While significant advances have been made for the treatment of advanced hepatocellular carcinoma in the past few years, the prognosis remains poor and effective biomarkers to guide selection of therapies [...] Read more.
Hepatocellular carcinoma (HCC) represents one of the leading causes of cancer mortality worldwide. While significant advances have been made for the treatment of advanced hepatocellular carcinoma in the past few years, the prognosis remains poor and effective biomarkers to guide selection of therapies remain noticeably absent. However, several targeted therapies have been approved in the past few years that have improved the outlook for this disease. In this review, we will highlight the recent therapies approved for the treatment of advanced HCC and discuss promising therapeutic options, targets, and pathways for drug development and consideration for future clinical trials. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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19 pages, 1610 KiB  
Review
ADAM-Mediated Signalling Pathways in Gastrointestinal Cancer Formation
by Neele Schumacher, Stefan Rose-John and Dirk Schmidt-Arras
Int. J. Mol. Sci. 2020, 21(14), 5133; https://doi.org/10.3390/ijms21145133 - 20 Jul 2020
Cited by 15 | Viewed by 3466
Abstract
Tumour growth is not solely driven by tumour cell-intrinsic mechanisms, but also depends on paracrine signals provided by the tumour micro-environment. These signals comprise cytokines and growth factors that are synthesized as trans-membrane proteins and need to be liberated by limited proteolysis also [...] Read more.
Tumour growth is not solely driven by tumour cell-intrinsic mechanisms, but also depends on paracrine signals provided by the tumour micro-environment. These signals comprise cytokines and growth factors that are synthesized as trans-membrane proteins and need to be liberated by limited proteolysis also termed ectodomain shedding. Members of the family of A disintegrin and metalloproteases (ADAM) are major mediators of ectodomain shedding and therefore initiators of paracrine signal transduction. In this review, we summarize the current knowledge on how ADAM proteases on tumour cells but also on cells of the tumour micro-environment contribute to the formation of gastrointestinal tumours, and discuss how these processes can be exploited pharmacologically. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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15 pages, 913 KiB  
Review
In Vivo Models for Cholangiocarcinoma—What Can We Learn for Human Disease?
by Raphael Mohr, Burcin Özdirik, Jana Knorr, Alexander Wree, Münevver Demir, Frank Tacke and Christoph Roderburg
Int. J. Mol. Sci. 2020, 21(14), 4993; https://doi.org/10.3390/ijms21144993 - 15 Jul 2020
Cited by 10 | Viewed by 5055
Abstract
Cholangiocarcinoma (CCA) comprises a heterogeneous group of primary liver tumors. They emerge from different hepatic (progenitor) cell populations, typically via sporadic mutations. Chronic biliary inflammation, as seen in primary sclerosing cholangitis (PSC), may trigger CCA development. Although several efforts were made in the [...] Read more.
Cholangiocarcinoma (CCA) comprises a heterogeneous group of primary liver tumors. They emerge from different hepatic (progenitor) cell populations, typically via sporadic mutations. Chronic biliary inflammation, as seen in primary sclerosing cholangitis (PSC), may trigger CCA development. Although several efforts were made in the last decade to better understand the complex processes of biliary carcinogenesis, it was only recently that new therapeutic advances have been achieved. Animal models are a crucial bridge between in vitro findings on molecular or genetic alterations, pathophysiological understanding, and new therapeutic strategies for the clinic. Nevertheless, it is inherently difficult to recapitulate simultaneously the stromal microenvironment (e.g., immune-competent cells, cholestasis, inflammation, PSC-like changes, fibrosis) and the tumor biology (e.g., mutational burden, local growth, and metastatic spread) in an animal model, so that it would reflect the full clinical reality of CCA. In this review, we highlight available data on animal models for CCA. We discuss if and how these models reflect human disease and whether they can serve as a tool for understanding the pathogenesis, or for predicting a treatment response in patients. In addition, open issues for future developments will be discussed. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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11 pages, 666 KiB  
Review
Percutaneous Ablation-Induced Immunomodulation in Hepatocellular Carcinoma
by Lucile Dumolard, Julien Ghelfi, Gael Roth, Thomas Decaens and Zuzana Macek Jilkova
Int. J. Mol. Sci. 2020, 21(12), 4398; https://doi.org/10.3390/ijms21124398 - 20 Jun 2020
Cited by 30 | Viewed by 4879
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide and its incidence is rising. Percutaneous locoregional therapies, such as radiofrequency ablation and microwave ablation, are widely used as curative treatment options for patients with small HCC, but their [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide and its incidence is rising. Percutaneous locoregional therapies, such as radiofrequency ablation and microwave ablation, are widely used as curative treatment options for patients with small HCC, but their effectiveness remains restricted because of the associated high rate of recurrence, occurring in about 70% of patients at five years. These thermal ablation techniques have the particularity to induce immunomodulation by destroying tumours, although this is not sufficient to raise an effective antitumour immune response. Ablative therapies combined with immunotherapies could act synergistically to enhance antitumour immunity. This review aims to understand the different immune changes triggered by radiofrequency ablation and microwave ablation as well as the interest in using immunotherapies in combination with thermal ablation techniques as a tool for complementary immunomodulation. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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40 pages, 1095 KiB  
Review
The Neuropeptide System and Colorectal Cancer Liver Metastases: Mechanisms and Management
by Aldona Kasprzak and Agnieszka Adamek
Int. J. Mol. Sci. 2020, 21(10), 3494; https://doi.org/10.3390/ijms21103494 - 15 May 2020
Cited by 23 | Viewed by 5713
Abstract
Colorectal cancer (CRC), classified as the third most prevalent cancer worldwide, remains to be a clinical and research challenge. It is estimated that ~50% of CRC patients die from distant metastases, with treatment of this complication still posing significant difficulties. While liver metastasis [...] Read more.
Colorectal cancer (CRC), classified as the third most prevalent cancer worldwide, remains to be a clinical and research challenge. It is estimated that ~50% of CRC patients die from distant metastases, with treatment of this complication still posing significant difficulties. While liver metastasis (LM) cascade is known in the literature, its mechanisms are still unclear and remain studied in different research models. A connection is suggested between nervous system dysfunctions and a range of Neurotransmitters (Nts) (including Neuropeptides, NPs), Neurotrophins (Ntt) and their receptors (Rs) in CRC liver metastasis development. Studies on the role of NP/NP-Rs in the progression and metastasis of CRC, show the complexity of brain–tumor interactions, caused by their different forms of release to the extracellular environment (endocrine, autocrine, paracrine and neurocrine). Many stages of LM are connected to the activity of pro-inflammatory, e.g., Corticotropin-releasing Hormone Receptor 1 (CRHR1), Neuropeptide Y (NPY) and Neurotensin (NT), anti-inflammatory, e.g., Calcitonin Gene-related Peptide (CGRP), CRHR2 and Vasoactive Intestinal Polypeptide (VIP) or dual role neuropeptides, e.g., Substance P (SP). The regulation of the local immunological profile (e.g., CRH/CRHRs), dysfunctions of enteroprotective role of NPs on epithelial cells (e.g., NT/NT-R), as well as structural-functional changes in enteric nervous system innervation of the tumor are also important. More research is needed to understand the exact mechanisms of communication between the neurons and tumor cells. The knowledge on the mechanisms regulating tumor growth and different stages of metastasis, as well as effects of the action of a numerous group of Nts/NPs/Ntt as growth factors, have implications for future therapeutic strategies. To obtain the best treatment outcomes, it is important to use signaling pathways common for many NPs, as well to develop a range of broad-spectrum antagonists. This review aims to summarize the current knowledge on the importance of neuroactive molecules in the promotion of the invasion-metastasis cascade in CRC, as well as the improvements of clinical management of CRC liver metastasis. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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20 pages, 1253 KiB  
Review
An Immunological Glance on Pancreatic Ductal Adenocarcinoma
by Michael Karl Melzer, Frank Arnold, Katja Stifter, Friedemann Zengerling, Ninel Azoitei, Thomas Seufferlein, Christian Bolenz and Alexander Kleger
Int. J. Mol. Sci. 2020, 21(9), 3345; https://doi.org/10.3390/ijms21093345 - 8 May 2020
Cited by 14 | Viewed by 4508
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has still a dismal prognosis. Different factors such as mutational landscape, intra- and intertumoral heterogeneity, stroma, and immune cells impact carcinogenesis of PDAC associated with an immunosuppressive microenvironment. Different cell types with partly opposing roles contribute to this milieu. [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) has still a dismal prognosis. Different factors such as mutational landscape, intra- and intertumoral heterogeneity, stroma, and immune cells impact carcinogenesis of PDAC associated with an immunosuppressive microenvironment. Different cell types with partly opposing roles contribute to this milieu. In recent years, immunotherapeutic approaches, including checkpoint inhibitors, were favored to treat cancers, albeit not every cancer entity exhibited benefits in a similar way. Indeed, immunotherapies rendered little success in pancreatic cancer. In this review, we describe the communication between the immune system and pancreatic cancer cells and propose some rationale why immunotherapies may fail in the context of pancreatic cancer. Moreover, we delineate putative strategies to sensitize PDAC towards immunological therapeutics and highlight the potential of targeting neoantigens. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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2 pages, 1173 KiB  
Correction
Correction: Alcalá, S., et al. Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells. Int. J. Mol. Sci. 2020, 21, 7437
by Sonia Alcalá, Víctor Mayoral-Varo, Laura Ruiz-Cañas, Juan Carlos López-Gil, Christopher Heeschen, Jorge Martín-Pérez and Bruno Sainz, Jr.
Int. J. Mol. Sci. 2020, 21(23), 9215; https://doi.org/10.3390/ijms21239215 - 3 Dec 2020
Cited by 2 | Viewed by 1668
Abstract
The authors recently reported on the potential of targeting SRC kinase signaling in pancreatic cancer stem cells [...] Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer)
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