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Loco-Regional Chemotherapy in Cancer: From Molecular Mechanisms to Therapies

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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 (31 December 2020) | Viewed by 21907

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Prof. Dr. Stefano Guadagni

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Guest Editor

Departement of Applied Clinical Sciences and Biotechnology, University of L'Aquila, via Vetoio, 67100 L'Aquila, Italy
Interests: surgical oncology; precision oncotherapy; colorectal cancer; skin cancers; loco-regional chemotherapy

Prof. Dr. Giammaria Fiorentini

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Guest Editor

Department of Oncology and Hematology , Azienda Ospedaliera Marche Nord, Pesaro, Italy
Interests: primary and metastatic liver tumors; intra-arterial chemotherapy; chemoembolization; hyperthermia; randomized trials; pancreatic tumors; brain tumors; peritoneal carcinomatosis

Special Issue Information

Dear Colleagues,

Locoregional chemotherapy takes advantage of an isolated blood supply to maximize local drug dose and intensity, enabling the specific treatment of localized disease whilst minimizing the potential for systemic side effects. However, despite encouraging results, locoregional chemotherapy does not feature in current therapeutic guidelines.

Impressive data have been reported for hepatic artery infusion (HAI), hyperthermic intraperitoneal chemotherapy (HIPEC), pressurized intraperitoneal aerosol chemotherapy (PIPAC), hyperthermic perfusions and hypoxic infusions, for the management of liver metastases, peritoneal metastases, limb-localized melanoma and sarcomas, and other cancers, adding to the treatment modalities that deserve further investigation.

The potential impact of predictive liquid biopsy precision oncotherapy on therapeutic selection is also of great potential importance but requires further investigation to arrive at a methodological consensus.

For this Special Issue, therefore, we request articles that develop molecular rather than purely clinical aspects of these treatment modalities and predictive techniques (e.g., chemotherapeutic action pharmacokinetics, molecular mechanisms of drug action, and/or the importance of tumor-specific gene mutation status characterization).

Prof. Dr. Stefano Guadagni
Prof. Dr. Giammaria Fiorentini
Guest Editors

Manuscript Submission Information

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Keywords

HAI
TACE
HIPEC
Hyperthermia
STOPFLOW
PIPAC
Detoxication
Precision oncotherapy
Circulating tumor cells
Liquid biopsies
Checkpoint inhibitors

Published Papers (6 papers)

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Research

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17 pages, 30504 KiB

Open AccessArticle

Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6–7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A

by Stefano Guadagni, Antonietta Rosella Farina, Lucia Annamaria Cappabianca, Michela Sebastiano, Rita Maccarone, Veronica Zelli, Marco Clementi, Alessandro Chiominto, Gemma Bruera, Enrico Ricevuto, Giammaria Fiorentini, Donatella Sarti and Andrew Reay Mackay

Int. J. Mol. Sci. 2020, 21(21), 8222; https://doi.org/10.3390/ijms21218222 - 03 Nov 2020

Cited by 4 | Viewed by 1948

Abstract

Merkel cell carcinomas (MCCs) are rare, aggressive, cutaneous neuroendocrine tumours, approximately 80% of which are caused by the genomic integration of Merkel cell polyomavirus (MCPyV). MCPyV-positive MCCs carry poor prognosis in approximately 70% of cases, highlighting the need for greater understanding of the oncogenic mechanisms involved in pathogenesis, progression and post-therapeutic relapse, and translation into novel therapeutic strategies. In a previous pilot study, we reported a potential relationship between MCPyV gene expression and oncogenic alternative Δ exon 6–7 TrkAIII splicing in formalin-fixed paraffin-embedded (FFPE) MCC tissues from a 12-patient cohort of >90% MCPyV-positive MCCs, diagnosed at San Salvatore Hospital, L’Aquila, Italy, characterising a new MCC subgroup and unveiling a novel potential MCPyV oncogenic mechanism and therapeutic target. This, however, could not be fully verified due to poor RNA quality and difficulty in protein extraction from FFPE tissues. Here, therefore, we extend our previous observations to confirm the relationship between MCPyV and oncogenic alternative Δ exon 6–7 TrkAIII splicing in fresh, nonfixed, MCPyV-positive MCC metastasis by detecting sequence-verified RT-PCR products, including full-length Δ exon 6–7 TrkAIII, and by Western blot detection of a 100 kDa TrkA protein isoform of identical size to 100 kDa Δ exon 6–7 TrkAIII expressed by stable transfected SH-SY5Y cells. We also report that in three MCC patients submitted for multidisciplinary treatment, including locoregional chemotherapy, MCPyV large T-antigen mRNA expression, Δ exon 6–7 TrkAIII mRNA expression and intracellular indirect immunofluorescence (IF) TrkA and phosphorylation protein isoform(s) immunoreactivity in FFPE tissues were not reduced in postchemotherapeutic-relapsed MCCs compared to pretherapeutic MCCs, extending the possible roles of this novel potential MCPyV oncogenic mechanism from MCC pathogenesis to post-therapeutic relapse and progression. Detection of alternative Δ exon 6–7 TrkAIII splicing in MCC, therefore, not only characterises a new MCPyV-positive MCC subgroup and unveils a novel potential MCPyV oncogenic mechanism but also identifies patients who may benefit from inhibitors of MCPyV T-antigen and/or TrkAIII expression or clinically approved Trk kinase inhibitors such as larotrectinib or entrectinib, which are known to inhibit activated TrkA oncogenes and to elicit durable responses in TrkA-fusion oncogene-driven cancers, supporting the call for a large-scale multicentre clinical study. Full article

(This article belongs to the Special Issue Loco-Regional Chemotherapy in Cancer: From Molecular Mechanisms to Therapies)

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16 pages, 3261 KiB

Open AccessArticle

Thrombocytosis and Effects of IL-6 Knock-Out in a Colitis-Associated Cancer Model

by Valeria Josa, Szilamer Ferenczi, Rita Szalai, Eniko Fuder, Daniel Kuti, Krisztina Horvath, Nikolett Hegedus, Tibor Kovacs, Gergo Bagamery, Balazs Juhasz, Zsuzsanna Winkler, Daniel S. Veres, Zsombor Zrubka, Domokos Mathe and Zsolt Baranyai

Int. J. Mol. Sci. 2020, 21(17), 6218; https://doi.org/10.3390/ijms21176218 - 27 Aug 2020

Cited by 11 | Viewed by 2728

Abstract

There is an increasing number of studies showing that thrombocytosis—accompanying a variety of solid tumors including colorectal cancer (CRC)—is associated with shorter survival and earlier development of metastases. The mechanisms of cancer-associated thrombocytosis are not completely understood yet. The aim of our study was to evaluate the role of IL-6 in tumor development and thrombocytosis in mice with inflammation-induced CRC, using a CRISPR/cas9 IL-6 knockout (KO) strain. Adult male FB/Ant mice (n = 39) were divided into four groups: (1) IL-6 KO controls (n = 5); (2) IL-6 KO CRC model group (n = 18); (3) Wild-type (WT) controls (n = 6); and (4) WT CRC model group (n = 10). CRC model animals in (2) and (4) received azoxymethane (AOM)/dextran sodium sulfate (DSS) treatment to induce inflammation-related CRC. Plasma and liver tissues were obtained to determine platelet counts, IL-6 and thrombopoietin-1 (TPO) levels. In 1 WT and 2 IL-6 KO mice in vivo confocal endomicroscopy and 18F-fluorodeoxyglucose (FDG) PET/MRI examinations were performed to evaluate the inflammatory burden and neoplastic transformation. At the end of the study, tumorous foci could be observed macroscopically in both CRC model groups. Platelet counts were significantly elevated in the WT CRC group compared to the IL-6 KO CRC group. TPO levels moved parallelly with platelet counts. In vivo fluorescent microscopy showed signs of disordered and multi-nuclear crypt morphology with increased mucus production in a WT animal, while regular mucosal structure was prominent in the IL-6 KO animals. The WT animal presented more intense and larger colonic FDG uptake than IL-6 KO animals. Our study confirmed thrombocytosis accompanying inflammation-related CRC and the crucial role of IL-6 in this process. Significantly higher platelet counts were found in the WT CRC group compared to both the control group and the IL-6 KO group. Concomitantly, the tumor burden of WT mice was also greater than that of IL-6 KO mice. Our findings are in line with earlier paraneoplastic IL-6 effect suggestions. Full article

(This article belongs to the Special Issue Loco-Regional Chemotherapy in Cancer: From Molecular Mechanisms to Therapies)

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15 pages, 5001 KiB

Open AccessArticle

Modulated Electro-Hyperthermia Resolves Radioresistance of Panc1 Pancreas Adenocarcinoma and Promotes DNA Damage and Apoptosis In Vitro

by Gertrud Forika, Andrea Balogh, Tamas Vancsik, Attila Zalatnai, Gabor Petovari, Zoltan Benyo and Tibor Krenacs

Int. J. Mol. Sci. 2020, 21(14), 5100; https://doi.org/10.3390/ijms21145100 - 19 Jul 2020

Cited by 6 | Viewed by 2851

Abstract

The poor outcome of pancreas ductal adenocarcinomas (PDAC) is frequently linked to therapy resistance. Modulated electro-hyperthermia (mEHT) generated by 13.56 MHz capacitive radiofrequency can induce direct tumor damage and promote chemo- and radiotherapy. Here, we tested the effect of mEHT either alone or in combination with radiotherapy using an in vivo model of Panc1, a KRAS and TP53 mutant, radioresistant PDAC cell line. A single mEHT shot of 60 min induced ~50% loss of viable cells and morphological signs of apoptosis including chromatin condensation, nuclear shrinkage and apoptotic bodies. Most mEHT treatment related effects exceeded those of radiotherapy, and these were further amplified after combining the two modalities. Treatment related apoptosis was confirmed by a significantly elevated number of annexin V single-positive and cleaved/activated caspase-3 positive tumor cells, as well as sub-G1-phase tumor cell fractions. mEHT and mEHT+radioterapy caused the moderate accumulation of γH2AX positive nuclear foci, indicating DNA double-strand breaks and upregulation of the cyclin dependent kinase inhibitor p21^waf1 besides the downregulation of Akt signaling. A clonogenic assay revealed that both mono- and combined treatments affected the tumor progenitor/stem cell populations too. In conclusion, mEHT treatment can contribute to tumor growth inhibition and apoptosis induction and resolve radioresistance of Panc1 PDAC cells. Full article

(This article belongs to the Special Issue Loco-Regional Chemotherapy in Cancer: From Molecular Mechanisms to Therapies)

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19 pages, 1542 KiB

Open AccessArticle

A Pilot Study of the Predictive Potential of Chemosensitivity and Gene Expression Assays Using Circulating Tumour Cells from Patients with Recurrent Ovarian Cancer

by Stefano Guadagni, Marco Clementi, Francesco Masedu, Giammaria Fiorentini, Donatella Sarti, Marcello Deraco, Shigeki Kusamura, Ioannis Papasotiriou, Panagiotis Apostolou, Karl Reinhard Aigner, Giuseppe Zavattieri, Antonietta Rossella Farina, Giuseppe Vizzielli, Giovanni Scambia and Andrew Reay Mackay

Int. J. Mol. Sci. 2020, 21(13), 4813; https://doi.org/10.3390/ijms21134813 - 07 Jul 2020

Cited by 18 | Viewed by 3647

Abstract

Circulating tumour cells (CTCs) from liquid biopsies are under current investigation in several cancers, including epithelial ovarian cancer (EOC) but face significant drawbacks in terms of non-standardised methodology, low viable cell numbers and accuracy of CTC identification. In this pilot study, we report that chemosensitivity assays using liquid biopsy-derived metastatic EOC CTCs, from 10 patients, nine with stage IIIC and one with stage IV disease, in progression after systemic chemotherapy, submitted for hypoxic isolated abdominal perfusion (HAP), are both feasible and useful in predicting response to therapy. Viable metastatic EOC CTCs (>5 cells/mL for all 10 blood samples), enriched by transient culture and identified by reverse transcription polymerase chain reaction (RT-PCR) and indirect immunofluorescence (IF), were subjected to flow cytometry-based Annexin V-PE assays for chemosensitivity to several chemotherapeutic agents and by RT-PCR for tumour gene expression profiling. Using a cut-off value of >80% cell death, CTC chemosensitivity tests were predictive of patient RECIST 1.1 responses to HAP therapy associated with 100% sensitivity, 50% specificity, 33% positive predictive, 100% negative predictive and 60% accuracy values. We propose that the methodology employed in this study is feasible and has the potential to predict response to therapy, setting the stage for a larger study. Full article

(This article belongs to the Special Issue Loco-Regional Chemotherapy in Cancer: From Molecular Mechanisms to Therapies)

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Review

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23 pages, 1868 KiB

Open AccessReview

Role of Epithelial–Mesenchymal Plasticity in Pseudomyxoma Peritonei: Implications for Locoregional Treatments

by Maria Luisa Calabrò, Nayana Lazzari, Giulia Rigotto, Marco Tonello and Antonio Sommariva

Int. J. Mol. Sci. 2020, 21(23), 9120; https://doi.org/10.3390/ijms21239120 - 30 Nov 2020

Cited by 6 | Viewed by 5594

Abstract

The mechanisms by which neoplastic cells disseminate from the primary tumor to metastatic sites, so-called metastatic organotropism, remain poorly understood. Epithelial–mesenchymal transition (EMT) plays a role in cancer development and progression by converting static epithelial cells into the migratory and microenvironment-interacting mesenchymal cells, and by the modulation of chemoresistance and stemness of tumor cells. Several findings highlight that pathways involved in EMT and its reverse process (mesenchymal–epithelial transition, MET), now collectively called epithelial–mesenchymal plasticity (EMP), play a role in peritoneal metastases. So far, the relevance of factors linked to EMP in a unique peritoneal malignancy such as pseudomyxoma peritonei (PMP) has not been fully elucidated. In this review, we focus on the role of epithelial–mesenchymal dynamics in the metastatic process involving mucinous neoplastic dissemination in the peritoneum. In particular, we discuss the role of expression profiles and phenotypic transitions found in PMP in light of the recent concept of EMP. A better understanding of EMP-associated mechanisms driving peritoneal metastasis will help to provide a more targeted approach for PMP patients selected for locoregional interventions involving cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Full article

(This article belongs to the Special Issue Loco-Regional Chemotherapy in Cancer: From Molecular Mechanisms to Therapies)

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25 pages, 6228 KiB

Open AccessReview

Modulated Electro-Hyperthermia-Induced Tumor Damage Mechanisms Revealed in Cancer Models

by Tibor Krenacs, Nora Meggyeshazi, Gertrud Forika, Eva Kiss, Peter Hamar, Tamas Szekely and Tamas Vancsik

Int. J. Mol. Sci. 2020, 21(17), 6270; https://doi.org/10.3390/ijms21176270 - 29 Aug 2020

Cited by 26 | Viewed by 4479

Abstract

The benefits of high-fever range hyperthermia have been utilized in medicine from the Ancient Greek culture to the present day. Amplitude-modulated electro-hyperthermia, induced by a 13.56 MHz radiofrequency current (mEHT, or Oncothermia), has been an emerging means of delivering loco-regional clinical hyperthermia as a complementary of radiation-, chemo-, and molecular targeted oncotherapy. This unique treatment exploits the metabolic shift in cancer, resulting in elevated oxidative glycolysis (Warburg effect), ion concentration, and electric conductivity. These promote the enrichment of electric fields and induce heat (controlled at 42 °C), as well as ion fluxes and disequilibrium through tumor cell membrane channels. By now, accumulating preclinical studies using in vitro and in vivo models of different cancer types have revealed details of the mechanism and molecular background of the oncoreductive effects of mEHT monotherapy. These include the induction of DNA double-strand breaks, irreversible heath and cell stress, and programmed cells death; the upregulation of molecular chaperones and damage (DAMP) signaling, which may contribute to a secondary immunogenic tumor cell death. In combination therapies, mEHT proved to be a good chemosensitizer through increasing drug uptake and tumor reductive effects, as well as a good radiosensitizer by downregulating hypoxia-related target genes. Recently, immune stimulation or intratumoral antigen-presenting dendritic cell injection have been able to extend the impact of local mEHT into a systemic “abscopal” effect. The complex network of pathways emerging from the published mEHT experiments has not been overviewed and arranged yet into a framework to reveal links between the pieces of the “puzzle”. In this paper, we review the mEHT-related damage mechanisms published in tumor models, which may allow some geno-/phenotype treatment efficiency correlations to be exploited both in further research and for more rational clinical treatment planning when mEHT is involved in combination therapies. Full article

(This article belongs to the Special Issue Loco-Regional Chemotherapy in Cancer: From Molecular Mechanisms to Therapies)

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