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Cancers
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Drug Resistance in Gastrointestinal Cancer
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Drug Resistance in Gastrointestinal Cancer

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

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 10575

Special Issue Editors

Dr. Rosalba D’Alessandro

E-Mail Website
Guest Editor
Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute for Digestive Diseases, IRCCS “Saverio de Bellis”, Via Turi 27, 70013 Castellana Grotte, BA, Italy
Interests: HCC; gastric cancer; target therapy; drug resistance; combined therapy; synergism; chemotherapeutic agents; growth factors; angiogenesis; cell cultures; proliferation; apoptosis; migration; signaling; PI3K/Akt; MAPK
Special Issues, Collections and Topics in MDPI journals
Dr. Carmelo Ferrai

E-Mail Website
Guest Editor
Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany
Interests: cell response to nanotopography; RNAPII & transcription regulation; chromatin conformation & nuclear architecture; pluripotency; cell plasticity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite recent advances in diagnosis and treatment, gastrointestinal cancer (GI) including tumors of various portions of the intestine, esophagus, stomach, liver, pancreas, and gallbladder is the leading cause of cancer deaths worldwide. According to the World Health Organization, the global burden of GI cancer accounts for 1 in 4 cancer cases and 1 in 3 cancer deaths.

While new therapies are now available, pathogenesis in gastrointestinal tumors remains elusive. Successful therapy thus depends on the combination of different therapeutic approaches, and the sequencing and timing of their administration are also crucial. However, the drug resistance in GI cancer still represents the main limiting factor that leads to a negative prognosis in patients. The heterogeneity of gastrointestinal tumors as well as the complex relationships between the tumor cell and its microenvironment is thought to represent the main determinant in the mechanisms of resistance.

Taking into account the pharmacological properties of the therapy, together with intrinsic and acquired physical and molecular parameters of tumor cells and extrinsic environmental factors, determining the spectrum of clinical responses is of utmost importance to develop successful therapy strategies.

We are pleased to invite you to contribute to the Special Issue “Drug Resistance in Gastrointestinal Cancer”. This SI aims to dissect the mechanisms of drug resistance through the analysis of its biological determinants, which could provide a useful map for its overall understanding. Original research articles and reviews are welcome. Research areas may include (but are not limited to) the following topics:

- Tumor heterogeneity studies (in bulk and single-cell analyses) and drug resistance;

- Analysis of the correlation between the molecular subtypes of gastrointestinal cancer and response to a given treatment;

- Elements of the microenvironment (immune system and mechano-transduction) that determine resistance to specific treatments;

- In-depth analysis of cancer drivers related to resistance mechanisms and novel drugs that could target them and produce a deeper response;

- Studies on the interaction mechanisms between drugs, analysis of the signal cascades involved, and synergic action;

- New predictive–prognostic biomarkers;

- Bioinformatic tools integrating clinical genomic data and computational modeling.

This combination of knowledge is expected to develop tools that inform real-time clinical decisions and continually improve through a feedback process based on the phenotypic outcomes observed.

I look forward to receiving your contributions.

Dr. Rosalba D’Alessandro
Dr. Carmelo Ferrai
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • gastrointestinal cancers
  • drug resistance
  • tumor heterogeneity
  • microenvironment
  • immune system
  • predictive biomarkers
  • combined therapy

Published Papers (6 papers)

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Research

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14 pages, 2385 KiB  
Article
Urokinase-Type Plasminogen Activator Receptor (uPAR) Cooperates with Mutated KRAS in Regulating Cellular Plasticity and Gemcitabine Response in Pancreatic Adenocarcinomas
by Luogen Peng, Yuchan Li, Sha Yao, Jochen Gaedcke, Victor M. Baart, Cornelis F. M. Sier, Albrecht Neesse, Volker Ellenrieder, Hanibal Bohnenberger, Frieder Fuchs, Julia Kitz, Philipp Ströbel and Stefan Küffer
Cancers 2023, 15(5), 1587; https://doi.org/10.3390/cancers15051587 - 03 Mar 2023
Cited by 2 | Viewed by 2376
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers. Given the currently limited therapeutic options, the definition of molecular subgroups with the development of tailored therapies remains the most promising strategy. Patients with high-level gene amplification of urokinase plasminogen activator [...] Read more.
Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers. Given the currently limited therapeutic options, the definition of molecular subgroups with the development of tailored therapies remains the most promising strategy. Patients with high-level gene amplification of urokinase plasminogen activator receptor (uPAR/PLAUR) have an inferior prognosis. We analyzed the uPAR function in PDAC to understand this understudied PDAC subgroup’s biology better. Methods: A total of 67 PDAC samples with clinical follow-up and TCGA gene expression data from 316 patients were used for prognostic correlations. Gene silencing by CRISPR/Cas9, as well as transfection of uPAR and mutated KRAS, were used in PDAC cell lines (AsPC-1, PANC-1, BxPC3) treated with gemcitabine to study the impact of these two molecules on cellular function and chemoresponse. HNF1A and KRT81 were surrogate markers for the exocrine-like and quasi-mesenchymal subgroup of PDAC, respectively. Results: High levels of uPAR were correlated with significantly shorter survival in PDAC, especially in the subgroup of HNF1A-positive exocrine-like tumors. uPAR knockout by CRISPR/Cas9 resulted in activation of FAK, CDC42, and p38, upregulation of epithelial makers, decreased cell growth and motility, and resistance against gemcitabine that could be reversed by re-expression of uPAR. Silencing of KRAS in AsPC1 using siRNAs reduced uPAR levels significantly, and transfection of mutated KRAS in BxPC-3 cells rendered the cell more mesenchymal and increased sensitivity towards gemcitabine. Conclusions: Activation of uPAR is a potent negative prognostic factor in PDAC. uPAR and KRAS cooperate in switching the tumor from a dormant epithelial to an active mesenchymal state, which likely explains the poor prognosis of PDAC with high uPAR. At the same time, the active mesenchymal state is more vulnerable to gemcitabine. Strategies targeting either KRAS or uPAR should consider this potential tumor-escape mechanism. Full article
(This article belongs to the Special Issue Drug Resistance in Gastrointestinal Cancer)
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14 pages, 492 KiB  
Article
Development of a Clinical–Biological Model to Assess Tumor Progression in Metastatic Pancreatic Cancer: Post Hoc Analysis of the PRODIGE4/ACCORD11 Trial
by Julie Egea, Julia Salleron, Sophie Gourgou, Ahmet Ayav, Valérie Laurent, Béata Juzyna, Alexandre Harlé, Thierry Conroy and Aurélien Lambert
Cancers 2022, 14(20), 5068; https://doi.org/10.3390/cancers14205068 - 16 Oct 2022
Viewed by 1201
Abstract
Background: The follow-up of pancreatic cancer (PC) is based on computed tomography (CT) assessment; however, there is no consensus on the use of clinical and biological criteria in tumor progression. We aimed to establish a clinical–biological model to highlight the progression of metastatic [...] Read more.
Background: The follow-up of pancreatic cancer (PC) is based on computed tomography (CT) assessment; however, there is no consensus on the use of clinical and biological criteria in tumor progression. We aimed to establish a clinical–biological model to highlight the progression of metastatic PC during first-line treatment. Methods: The patients treated with first-line chemotherapy in the phase 2/3 PRODIGE4/ACCORD11 clinical trial were evaluated retrospectively. Clinical and biological markers were evaluated at the time of CT scans and during treatment to determine tumor progression. Results: In total, 196 patients were analyzed, with 355 available tumor assessments. The clinical and biological factors associated with tumor progression in multivariate analysis included gemcitabine, global health status ≤ 33 (OR = 3.38, 95%CI [1.15; 9.91], p = 0.028), quality of life score between 34 and 66 (OR = 2.65, 95%CI [1.06; 6.59], p = 0.037), carcinoembryonic antigen (CEA) ≥ 3 times the standard value without any increase in the CEA level from inclusion (OR = 2.22, 95%CI [1.01; 4.89], p = 0.048) and with an increase in the CEA level from inclusion (OR = 6.56, 95%CI [2.73; 15.78], p < 0.001), and an increase in the carbohydrate antigen 19-9 level from inclusion (OR = 2.59, 95%CI [1.25; 5.36], p = 0.016). Conclusions: The self-assessment of patients’ general health status alongside tumor markers is an interesting approach to the diagnosis of the tumor progression of metastatic pancreatic cancer patients during first-line treatment. Full article
(This article belongs to the Special Issue Drug Resistance in Gastrointestinal Cancer)
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Review

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30 pages, 2750 KiB  
Review
Implications of Rectal Cancer Radiotherapy on the Immune Microenvironment: Allies and Foes to Therapy Resistance and Patients’ Outcome
by Dorothée Sartorius, Moritz Leander Blume, Johannes Robert Fleischer, Michael Ghadimi, Lena-Christin Conradi and Tiago De Oliveira
Cancers 2023, 15(21), 5124; https://doi.org/10.3390/cancers15215124 - 24 Oct 2023
Cited by 1 | Viewed by 1238
Abstract
Aside from surgical resection, locally advanced rectal cancer is regularly treated with neoadjuvant chemoradiotherapy. Since the concept of cancer treatment has shifted from only focusing on tumor cells as drivers of disease progression towards a broader understanding including the dynamic tumor microenvironment (TME), [...] Read more.
Aside from surgical resection, locally advanced rectal cancer is regularly treated with neoadjuvant chemoradiotherapy. Since the concept of cancer treatment has shifted from only focusing on tumor cells as drivers of disease progression towards a broader understanding including the dynamic tumor microenvironment (TME), the impact of radiotherapy on the TME and specifically the tumor immune microenvironment (TIME) is increasingly recognized. Both promoting as well as suppressing effects on anti-tumor immunity have been reported in response to rectal cancer (chemo-)radiotherapy and various targets for combination therapies are under investigation. A literature review was conducted searching the PubMed database for evidence regarding the pleiotropic effects of (chemo-)radiotherapy on the rectal cancer TIME, including alterations in cytokine levels, immune cell populations and activity as well as changes in immune checkpoint proteins. Radiotherapy can induce immune-stimulating and -suppressive alterations, potentially mediating radioresistance. The response is influenced by treatment modalities, including the dosage administered and the highly individual intrinsic pre-treatment immune status. Directly addressing the main immune cells of the TME, this review aims to highlight therapeutical implications since efficient rectal cancer treatment relies on personalized strategies combining conventional therapies with immune-modulating approaches, such as immune checkpoint inhibitors. Full article
(This article belongs to the Special Issue Drug Resistance in Gastrointestinal Cancer)
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18 pages, 2003 KiB  
Review
Histone and DNA Methylation as Epigenetic Regulators of DNA Damage Repair in Gastric Cancer and Emerging Therapeutic Opportunities
by Katia De Marco, Paola Sanese, Cristiano Simone and Valentina Grossi
Cancers 2023, 15(20), 4976; https://doi.org/10.3390/cancers15204976 - 13 Oct 2023
Viewed by 1376
Abstract
Gastric cancer (GC), one of the most common malignancies worldwide, is a heterogeneous disease developing from the accumulation of genetic and epigenetic changes. One of the most critical epigenetic alterations in GC is DNA and histone methylation, which affects multiple processes in the [...] Read more.
Gastric cancer (GC), one of the most common malignancies worldwide, is a heterogeneous disease developing from the accumulation of genetic and epigenetic changes. One of the most critical epigenetic alterations in GC is DNA and histone methylation, which affects multiple processes in the cell nucleus, including gene expression and DNA damage repair (DDR). Indeed, the aberrant expression of histone methyltransferases and demethylases influences chromatin accessibility to the DNA repair machinery; moreover, overexpression of DNA methyltransferases results in promoter hypermethylation, which can suppress the transcription of genes involved in DNA repair. Several DDR mechanisms have been recognized so far, with homologous recombination (HR) being the main pathway involved in the repair of double-strand breaks. An increasing number of defective HR genes are emerging in GC, resulting in the identification of important determinants of therapeutic response to DDR inhibitors. This review describes how both histone and DNA methylation affect DDR in the context of GC and discusses how alterations in DDR can help identify new molecular targets to devise more effective therapeutic strategies for GC, with a particular focus on HR-deficient tumors. Full article
(This article belongs to the Special Issue Drug Resistance in Gastrointestinal Cancer)
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15 pages, 1118 KiB  
Review
Targeting Angiogenesis in the Era of Biliary Tract Cancer Immunotherapy: Biological Rationale, Clinical Implications, and Future Research Avenues
by Annalisa Schirizzi, Giampiero De Leonardis, Vincenza Lorusso, Rossella Donghia, Alessandro Rizzo, Simona Vallarelli, Carmela Ostuni, Laura Troiani, Ivan Roberto Lolli, Gianluigi Giannelli, Angela Dalia Ricci, Rosalba D’Alessandro and Claudio Lotesoriere
Cancers 2023, 15(8), 2376; https://doi.org/10.3390/cancers15082376 - 19 Apr 2023
Cited by 1 | Viewed by 1587
Abstract
Although biliary tract cancers are traditionally considered rare in Western countries, their incidence and mortality rates are rising worldwide. A better knowledge of the genomic landscape of these tumor types has broadened the number of molecular targeted therapies, including angiogenesis inhibitors. The role [...] Read more.
Although biliary tract cancers are traditionally considered rare in Western countries, their incidence and mortality rates are rising worldwide. A better knowledge of the genomic landscape of these tumor types has broadened the number of molecular targeted therapies, including angiogenesis inhibitors. The role of immune checkpoint inhibitors (ICIs) could potentially change the first-line therapeutic approach, but monotherapy with ICIs has shown disappointing results in CCA. Several clinical trials are evaluating combination strategies that include immunotherapy together with other anticancer agents with a synergistic activity. The tumor microenvironment (TME) composition plays a pivotal role in the prognosis of BTC patients. The accumulation of immunosuppressive cell types, such as tumor-associated macrophages (TAMs) and regulatory T-cells, together with the poor infiltration of cytotoxic CD8+ T-cells, is known to predispose to a poor prognosis owing to the establishment of resistance mechanisms. Likewise, angiogenesis is recognized as a major player in modulating the TME in an immunosuppressive manner. This is the mechanistic rationale for combination treatment schemes blocking both immunity and angiogenesis. In this scenario, this review aims to provide an overview of the most recent completed or ongoing clinical trials combining immunotherapy and angiogenesis inhibitors with/without a chemotherapy backbone. Full article
(This article belongs to the Special Issue Drug Resistance in Gastrointestinal Cancer)
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20 pages, 2393 KiB  
Review
microRNAs Associated with Gemcitabine Resistance via EMT, TME, and Drug Metabolism in Pancreatic Cancer
by Naotake Funamizu, Masahiko Honjo, Kei Tamura, Katsunori Sakamoto, Kohei Ogawa and Yasutsugu Takada
Cancers 2023, 15(4), 1230; https://doi.org/10.3390/cancers15041230 - 15 Feb 2023
Cited by 4 | Viewed by 1987
Abstract
Despite extensive research, pancreatic cancer remains a lethal disease with an extremely poor prognosis. The difficulty in early detection and chemoresistance to therapeutic agents are major clinical concerns. To improve prognosis, novel biomarkers, and therapeutic strategies for chemoresistance are urgently needed. microRNAs (miRNAs) [...] Read more.
Despite extensive research, pancreatic cancer remains a lethal disease with an extremely poor prognosis. The difficulty in early detection and chemoresistance to therapeutic agents are major clinical concerns. To improve prognosis, novel biomarkers, and therapeutic strategies for chemoresistance are urgently needed. microRNAs (miRNAs) play important roles in the development, progression, and metastasis of several cancers. During the last few decades, the association between pancreatic cancer and miRNAs has been extensively elucidated, with several miRNAs found to be correlated with patient prognosis. Moreover, recent evidence has revealed that miRNAs are intimately involved in gemcitabine sensitivity and resistance through epithelial-to-mesenchymal transition, the tumor microenvironment, and drug metabolism. Gemcitabine is the gold standard drug for pancreatic cancer treatment, but gemcitabine resistance develops easily after chemotherapy initiation. Therefore, in this review, we summarize the gemcitabine resistance mechanisms associated with aberrantly expressed miRNAs in pancreatic cancer, especially focusing on the mechanisms associated with epithelial-to-mesenchymal transition, the tumor microenvironment, and metabolism. This novel evidence of gemcitabine resistance will drive further research to elucidate the mechanisms of chemoresistance and improve patient outcomes. Full article
(This article belongs to the Special Issue Drug Resistance in Gastrointestinal Cancer)
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