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New Treatment for Colorectal Cancer
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New Treatment for Colorectal Cancer

A topical collection in Cancers (ISSN 2072-6694). This collection belongs to the section "Cancer Therapy".

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Editor

Prof. Dr. Antonio V. Sterpetti

E-Mail Website
Guest Editor
Department of Surgery “Pietro Valdoni”, Sapienza, University of Rome, 00161 Rome, Italy
Interests: colorectal cancer; therapy; inflammation; aging
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Colorectal cancer incidence rates vary greatly by world region. The disease is considered to be a marker of socioeconomic development and, in countries undergoing a major development transition, incidence rates tend to rise. These increases in incidence have been ascribed to the new western lifestyle, which is correlated with economic improvements, prolonged life expectancy, and aging. There is evidence that processed meat, alcohol, and obesity increase the risk for sporadic colon cancer, whereas physical activity is protective. Epidemiologic studies in the last few decades have noted, in some countries, such as Russia and China, increases in both incidence and mortality. In other countries, such as Canada and the United Kingdom, there has been an increase in incidence but a decrease in mortality. In the United States, Japan, and several western European countries, a reduction in incidence and mortality has been reported. A decrease in incidence has been registered for patients older than 60 years, who represent the majority of patients with colon cancer. Moreover, there has been an increase in incidence and mortality for patients younger than 50 years in the United States and western European countries.

New screening modalities and more effective therapeutic approaches, including specific anti-inflammatory drugs, have the potential to reduce the incidence of mortality due to this common disease.

In this Special Issue, we would like to summarize recent advances in colorectal cancer research that may lead to more effective prevention and therapy.

Prof. Antonio V. Sterpetti
Guest Editor

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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

  • colorectal cancer
  • therapy
  • inflammation
  • aging

Published Papers (17 papers)

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2023

Jump to: 2022, 2021

17 pages, 4174 KiB  
Article
Mannose Inhibits the Pentose Phosphate Pathway in Colorectal Cancer and Enhances Sensitivity to 5-Fluorouracil Therapy
by Sadaf Al Hadeethi, Chirine El-Baba, Khaled Araji, Berthe Hayar, Israa Ahmad Cheikh, Riyad El-Khoury, Julnar Usta and Nadine Darwiche
Cancers 2023, 15(8), 2268; https://doi.org/10.3390/cancers15082268 - 13 Apr 2023
Cited by 1 | Viewed by 2215
Abstract
Colorectal cancer (CRC) is one of the leading cancers and causes of death in patients. 5-fluorouracil (5-FU) is the therapy of choice for CRC, but it exhibits high toxicity and drug resistance. Tumorigenesis is characterized by a deregulated metabolism, which promotes cancer cell [...] Read more.
Colorectal cancer (CRC) is one of the leading cancers and causes of death in patients. 5-fluorouracil (5-FU) is the therapy of choice for CRC, but it exhibits high toxicity and drug resistance. Tumorigenesis is characterized by a deregulated metabolism, which promotes cancer cell growth and survival. The pentose phosphate pathway (PPP) is required for the synthesis of ribonucleotides and the regulation of reactive oxygen species and is upregulated in CRC. Mannose was recently reported to halt tumor growth and impair the PPP. Mannose inhibitory effects on tumor growth are inversely related to the levels of phosphomannose isomerase (PMI). An in silico analysis showed low PMI levels in human CRC tissues. We, therefore, investigated the effect of mannose alone or in combination with 5-FU in human CRC cell lines with different p53 and 5-FU resistance statuses. Mannose resulted in a dose-dependent inhibition of cell growth and synergized with 5-FU treatment in all tested cancer cell lines. Mannose alone or in combination with 5-FU reduced the total dehydrogenase activity of key PPP enzymes, enhanced oxidative stress, and induced DNA damage in CRC cells. Importantly, single mannose or combination treatments with 5-FU were well tolerated and reduced tumor volumes in a mouse xenograft model. In summary, mannose alone or in combination with 5-FU may represent a novel therapeutic strategy in CRC. Full article
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2022

Jump to: 2023, 2021

17 pages, 3697 KiB  
Article
The Novel IGF-1R Inhibitor PB-020 Acts Synergistically with Anti-PD-1 and Mebendazole against Colorectal Cancer
by Bo Kang, Xiaobing Zhang, Weibing Wang, Shiqi She, Wenjie Chen, Cheng Chen, Yisha Wang, Xiaoyun Pan, Ouyuan Xu and Yingjie Wang
Cancers 2022, 14(23), 5747; https://doi.org/10.3390/cancers14235747 - 23 Nov 2022
Cited by 3 | Viewed by 1606
Abstract
CRC is one of the leading causes of cancer mortality worldwide. Chemotherapy is widely used for the treatment of CRC, but its efficacy remains unsatisfactory, mainly due to drug resistance. Therefore, it is urgent to develop new strategies to overcome drug resistance. Combination [...] Read more.
CRC is one of the leading causes of cancer mortality worldwide. Chemotherapy is widely used for the treatment of CRC, but its efficacy remains unsatisfactory, mainly due to drug resistance. Therefore, it is urgent to develop new strategies to overcome drug resistance. Combination therapy that aims to achieve additive or synergistic therapeutic effects is an effective approach to tackle the development of drug resistance. Given its established roles in tumor development, progression and metastasis, IGF-1R is a promising drug target for combination therapy against CRC. In this study, we revealed that the novel IGF-1R inhibitor PB-020 can act synergistically with mebendazole (MBZ) to reduce the viability of CRC cells and block xenograft CRC progression. Moreover, the PB-020/anti-PD-1 combination synergistically blocked CRC propagation in the MC38 murine colon carcinoma model. Both combination therapies potently suppressed the PI3K/AKT signaling pathway genes in CRC that may be associated with the development of drug resistance. Our findings establish a preclinical proof-of-concept for combating CRC using combined multi-target treatment with PB-020 and clinical anticancer drugs, which may provide useful clues for clinical trials to evaluate the efficacy and safety of these drug combinations in CRC patients. Full article
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12 pages, 978 KiB  
Review
The Role of Programmed Necrosis in Colorectal Cancer
by Yu-Qiang Yu, Reyes Gamez-Belmonte, Jay V. Patankar, Eva Liebing and Christoph Becker
Cancers 2022, 14(17), 4295; https://doi.org/10.3390/cancers14174295 - 01 Sep 2022
Cited by 5 | Viewed by 2768
Abstract
For quite a long time, necrosis was considered a chaotic and unorganized form of cell death. However, studies conducted during the past few decades unveiled multiple types of programmed necrosis, such as necroptosis, pyroptosis and ferroptosis. These types of programmed necrosis have been [...] Read more.
For quite a long time, necrosis was considered a chaotic and unorganized form of cell death. However, studies conducted during the past few decades unveiled multiple types of programmed necrosis, such as necroptosis, pyroptosis and ferroptosis. These types of programmed necrosis have been shown to play crucial roles in mediating pathological processes, including tumorigenesis. Almost all key mediators, such as RIPK3 and MLKL in necroptosis, GSDMD and caspase 1/11 in pyroptosis and GPX4 in ferroptosis, are highly expressed in intestinal epithelial cells (IECs). An aberrant increase or decrease in programmed necrosis in IECs has been connected to intestinal disorders. Here, we review the pathways of programmed necrosis and the specific consequences of regulated necrosis in colorectal cancer (CRC) development. Translational aspects of programmed necrosis induction as a novel therapeutic alternative against CRC are also discussed. Full article
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10 pages, 587 KiB  
Systematic Review
The Role of Indocyanine Green Fluorescence in Rectal Cancer Robotic Surgery: A Narrative Review
by Elena Belloni, Edoardo Maria Muttillo, Salomone Di Saverio, Marcello Gasparrini, Antonio Brescia and Giuseppe Nigri
Cancers 2022, 14(10), 2411; https://doi.org/10.3390/cancers14102411 - 13 May 2022
Cited by 8 | Viewed by 1810
Abstract
Background: In rectal cancer surgery, anastomotic leakage (AL) remains the most feared complication, with a frequency of up to 30% in non-high-volume centers. The preservation of proper vascularization is a key factor for successful anastomosis. The use of fluorescence with indocyanine green (ICG) [...] Read more.
Background: In rectal cancer surgery, anastomotic leakage (AL) remains the most feared complication, with a frequency of up to 30% in non-high-volume centers. The preservation of proper vascularization is a key factor for successful anastomosis. The use of fluorescence with indocyanine green (ICG) as an intraoperative method to verify optimal perfusion is becoming an interesting tool in rectal surgery. Today, robotic surgery, together with the use of the intraoperative evaluation of the perfusion with ICG, could be a real strategy to deal with AL, allowing for a more delicate and less traumatic surgical technique. This strategy may allow for an extremely accurate surgery, and for optimal control of the proper vascularization of the rectum. Methods: The purpose of this descriptive review is to analyze the impact of fluorescence and robotic surgery on short-term surgical outcomes for rectal cancer. Results: We performed a systematic literature search using the PubMed, Embase and Cochrane library databases. The primary endpoints were to evaluate the application of ICG fluorescence in robotic rectal surgery and the rate of anastomotic leakage when using these technological implementations. The secondary endpoints were to evaluate the dosage of ICG and the timing of application by different surgeons. Conclusions: ICG fluorescence is an inexpensive and quick method to assess bowel perfusion, providing immediate feedback to the surgeon, even if its role has not been proven. A quantitative system must be systematically introduced to minimize the subjectiveness of the visualized image. Full article
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18 pages, 740 KiB  
Review
Overcoming Therapy Resistance in Colon Cancer by Drug Repurposing
by Talal El Zarif, Marcel Yibirin, Diana De Oliveira-Gomes, Marc Machaalani, Rashad Nawfal, Gianfranco Bittar, Hisham F. Bahmad and Nizar Bitar
Cancers 2022, 14(9), 2105; https://doi.org/10.3390/cancers14092105 - 23 Apr 2022
Cited by 17 | Viewed by 4573
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world. Despite improvement in standardized screening methods and the development of promising therapies, the 5-year survival rates are as low as 10% in the metastatic setting. The increasing life expectancy of the [...] Read more.
Colorectal cancer (CRC) is the third most common cancer in the world. Despite improvement in standardized screening methods and the development of promising therapies, the 5-year survival rates are as low as 10% in the metastatic setting. The increasing life expectancy of the general population, higher rates of obesity, poor diet, and comorbidities contribute to the increasing trends in incidence. Drug repurposing offers an affordable solution to achieve new indications for previously approved drugs that could play a protagonist or adjuvant role in the treatment of CRC with the advantage of treating underlying comorbidities and decreasing chemotherapy toxicity. This review elaborates on the current data that supports drug repurposing as a feasible option for patients with CRC with a focus on the evidence and mechanism of action promising repurposed candidates that are widely used, including but not limited to anti-malarial, anti-helminthic, anti-inflammatory, anti-hypertensive, anti-hyperlipidemic, and anti-diabetic agents. Full article
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24 pages, 9440 KiB  
Article
In Vivo and In Vitro Enhanced Tumoricidal Effects of Metformin, Active Vitamin D3, and 5-Fluorouracil Triple Therapy against Colon Cancer by Modulating the PI3K/Akt/PTEN/mTOR Network
by Riyad Adnan Almaimani, Akhmed Aslam, Jawwad Ahmad, Mahmoud Zaki El-Readi, Mohamed E. El-Boshy, Abdelghany H. Abdelghany, Shakir Idris, Mai Alhadrami, Mohammad Althubiti, Hussain A. Almasmoum, Mazen M. Ghaith, Mohamed E. Elzubeir, Safaa Yehia Eid and Bassem Refaat
Cancers 2022, 14(6), 1538; https://doi.org/10.3390/cancers14061538 - 17 Mar 2022
Cited by 13 | Viewed by 3407
Abstract
Chemoresistance to 5-fluorouracil (5-FU) is common during colorectal cancer (CRC) treatment. This study measured the chemotherapeutic effects of 5-FU, active vitamin D3 (VD3), and/or metformin single/dual/triple regimens as complementary/alternative therapies. Ninety male mice were divided into: negative and positive (PC) [...] Read more.
Chemoresistance to 5-fluorouracil (5-FU) is common during colorectal cancer (CRC) treatment. This study measured the chemotherapeutic effects of 5-FU, active vitamin D3 (VD3), and/or metformin single/dual/triple regimens as complementary/alternative therapies. Ninety male mice were divided into: negative and positive (PC) controls, and 5-FU, VD3, Met, 5-FU/VD3, 5-FU/Met, VD3/Met, and 5-FU/VD3/Met groups. Treatments lasted four weeks following CRC induction by azoxymethane. Similar regimens were also applied in the SW480 and SW620 CRC cell lines. The PC mice had abundant tumours, markedly elevated proliferation markers (survivin/CCND1) and PI3K/Akt/mTOR, and reduced p21/PTEN/cytochrome C/caspase-3 and apoptosis. All therapies reduced tumour numbers, with 5-FU/VD3/Met being the most efficacious regimen. All protocols decreased cell proliferation markers, inhibited PI3K/Akt/mTOR molecules, and increased proapoptotic molecules with an apoptosis index, and 5-FU/VD3/Met revealed the strongest effects. In vitro, all therapies equally induced G1 phase arrest in SW480 cells, whereas metformin-alone showed maximal SW620 cell numbers in the G0/G1 phase. 5-FU/Met co-therapy also showed the highest apoptotic SW480 cell numbers (13%), whilst 5-FU/VD3/Met disclosed the lowest viable SW620 cell percentages (81%). Moreover, 5-FU/VD3/Met revealed maximal inhibitions of cell cycle inducers (CCND1/CCND3), cell survival (BCL2), and the PI3K/Akt/mTOR molecules alongside the highest expression of cell cycle inhibitors (p21/p27), proapoptotic markers (BAX/cytochrome C/caspase-3), and PTEN in both cell lines. In conclusion, metformin monotherapy was superior to VD3, whereas the 5-FU/Met protocol showed better anticancer effects relative to the other dual therapies. However, the 5-FU/VD3/Met approach displayed the best in vivo and in vitro tumoricidal effects related to cell cycle arrest and apoptosis, justifiably by enhanced modulations of the PI3K/PTEN/Akt/mTOR pathway. Full article
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12 pages, 6404 KiB  
Article
Border Line Definition Using Hyperspectral Imaging in Colorectal Resections
by Boris Jansen-Winkeln, Michelle Dvorak, Hannes Köhler, Marianne Maktabi, Matthias Mehdorn, Claire Chalopin, Michele Diana, Ines Gockel and Manuel Barberio
Cancers 2022, 14(5), 1188; https://doi.org/10.3390/cancers14051188 - 25 Feb 2022
Cited by 11 | Viewed by 1543
Abstract
Background: A perfusion deficit is a well-defined and intraoperatively influenceable cause of anastomotic leak (AL). Current intraoperative perfusion assessment methods do not provide objective and quantitative results. In this study, the ability of hyperspectral imaging (HSI) to quantify tissue oxygenation intraoperatively was assessed. [...] Read more.
Background: A perfusion deficit is a well-defined and intraoperatively influenceable cause of anastomotic leak (AL). Current intraoperative perfusion assessment methods do not provide objective and quantitative results. In this study, the ability of hyperspectral imaging (HSI) to quantify tissue oxygenation intraoperatively was assessed. Methods: 115 patients undergoing colorectal resections were included in the final analysis. Before anastomotic formation, the bowel was extracted and the resection line was outlined and imaged using a compact HSI camera, in order to provide instantaneously quantitative perfusion assessment. Results: In 105 patients, a clear demarcation line was visible with HSI one minute after marginal artery transection, reaching a plateau after 3 min. In 58 (55.2%) patients, the clinically determined transection line matched with HSI. In 23 (21.9%) patients, the clinically established resection margin was entirely within the less perfused area. In 24 patients (22.8%), the HSI transection line had an irregular course and crossed the clinically established resection line. In four cases, HSI disclosed a clinically undetected lesion of the marginal artery. Conclusions: Intraoperative HSI is safe, well reproducible, and does not disrupt the surgical workflow. It also quantifies bowel surface perfusion. HSI might become an intraoperative guidance tool, potentially preventing postoperative complications. Full article
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35 pages, 7951 KiB  
Review
Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers
by Lindsey Carlsen, Kelsey E. Huntington and Wafik S. El-Deiry
Cancers 2022, 14(4), 1028; https://doi.org/10.3390/cancers14041028 - 17 Feb 2022
Cited by 23 | Viewed by 5755
Abstract
Though early-stage colorectal cancer has a high 5 year survival rate of 65–92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients [...] Read more.
Though early-stage colorectal cancer has a high 5 year survival rate of 65–92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair-proficient patients to immunotherapy. Full article
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12 pages, 454 KiB  
Article
RAS Mutation Conversion in Bevacizumab-Treated Metastatic Colorectal Cancer Patients: A Liquid Biopsy Based Study
by Chiara Nicolazzo, Francesca Belardinilli, Annarita Vestri, Valentina Magri, Gianluigi De Renzi, Michela De Meo, Salvatore Caponnetto, Federica Di Nicolantonio, Enrico Cortesi, Giuseppe Giannini and Paola Gazzaniga
Cancers 2022, 14(3), 802; https://doi.org/10.3390/cancers14030802 - 04 Feb 2022
Cited by 8 | Viewed by 1957
Abstract
Liquid biopsies have shown that, in RAS mutant colorectal cancer, the conversion to RAS wild-type * status during the course of the disease is a frequent event, supporting the concept that the evolutionary landscape of colorectal cancer can lead to an unexpected negative [...] Read more.
Liquid biopsies have shown that, in RAS mutant colorectal cancer, the conversion to RAS wild-type * status during the course of the disease is a frequent event, supporting the concept that the evolutionary landscape of colorectal cancer can lead to an unexpected negative selection of RAS mutant clones. The aim of the present study was to clarify whether the negative selection of RAS mutation in plasma might be drug-dependent. For this purpose, we used liquid biopsy to compare the rate of conversion from RAS mutant to RAS wild-type * in two groups of originally RAS mutant mCRC patients: the first treated with chemotherapy alone, while the second was treated with chemotherapy combined with bevacizumab. Serial liquid biopsies were performed at 3 months (T1), 6 months (T2), 9 months (T3), and 12 months (T4) after starting first line treatments. We found that the only independent variable significantly associated to RAS status conversion was the use of bevacizumab. RAS conversion was not found associated to tumor burden reduction, although bevacizumab-treated patients who converted to RAS wild-type * had a significantly longer PFS compared to patients who remained RAS mutant. The appearance of a “RAS wild-type * window”, mainly in bevacizumab-treated patients, might present them as candidates for second line treatment with anti-EGFR, which was otherwise precluded. Full article
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2021

Jump to: 2023, 2022

12 pages, 1006 KiB  
Article
Deciphering Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Reveals the Poor Prognostic Factor of RASSF2 Gene Silencing in Colon Cancers
by Marc Riffet, Yassine Eid, Maxime Faisant, Audrey Fohlen, Benjamin Menahem, Arnaud Alves, Fatéméh Dubois, Guénaelle Levallet and Céline Bazille
Cancers 2021, 13(23), 5957; https://doi.org/10.3390/cancers13235957 - 26 Nov 2021
Cited by 2 | Viewed by 1674
Abstract
The aims of this study were to assess the frequency of promoter hypermethylation of the genes encoding the Ras associated domain family (RASSF)/Hippo pathway, as well as the impact on overall (OS) and progression-free survival (PFS) in a single-center retrospective cohort of 229 [...] Read more.
The aims of this study were to assess the frequency of promoter hypermethylation of the genes encoding the Ras associated domain family (RASSF)/Hippo pathway, as well as the impact on overall (OS) and progression-free survival (PFS) in a single-center retrospective cohort of 229 patients operated on for colon cancers. Hypermethylation status was investigated by methylation-specific PCR on the promoters of the RASSF1/2, STK4/3 (encoding Mammalian Ste20-like protein 1 and 2 (MST1 and 2), respectively), and LATS1/2 genes. Clinicopathological characteristics, recurrence-free survival, and overall survival were analysed. We found the RASSF/Hippo pathway to be highly silenced in colon cancer, and particularly RASSF2 (86%). The other promoters were hypermethylated with a lesser frequency of 16, 3, 1, 10 and 6%, respectively for RASSF1, STK4, STK3, LATS1, and LATS2 genes. As the hypermethylation of one RASSF/Hippo family member was by no means exclusive from the others, 27% of colon cancers displayed the hypermethylation of at least two RASSF/Hippo member promotors. The median overall survival of the cohort was 60.2 months, and the median recurrence-free survival was 46.9 months. Survival analyses showed a significantly poorer overall survival of patients when the RASSF2 promoter was hypermethylated (p = 0.03). The median OS was 53.5 months for patients with colon cancer with a hypermethylated RASSF2 promoter versus still not reached after 80 months follow-up for other patients, upon univariate analysis (HR = 1.86, [95% CI: 1.05–3.3], p < 0.03). Such difference was not significant for relapse-free survival as in multivariate analysis. A logistic regression model showed that RASSF2 hypermethylation was an independent factor. In conclusion, RASSF2 hypermethylation is a frequent event and an independent poor prognostic factor in colon cancer. This biomarker could be investigated in clinical practice. Full article
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16 pages, 2849 KiB  
Article
Nobiletin and Xanthohumol Sensitize Colorectal Cancer Stem Cells to Standard Chemotherapy
by Alice Turdo, Antonino Glaviano, Giacomo Pepe, Federica Calapà, Stefania Raimondo, Micol Eleonora Fiori, Daniela Carbone, Manuela Giovanna Basilicata, Veronica Di Sarno, Carmine Ostacolo, Barbara Parrino, Stella Cascioferro, Camilla Pecoraro, Simone Di Franco, Diana Bellavia, Miriam Gaggianesi, Veronica Veschi, Melania Lo Iacono, Gloria Ganduscio, Vincenzo Davide Pantina, Laura Rosa Mangiapane, Maria Rita Bongiorno, Riccardo Alessandro, Matilde Todaro, Ruggero De Maria, Patrizia Diana, Pietro Campiglia and Giorgio Stassiadd Show full author list remove Hide full author list
Cancers 2021, 13(16), 3927; https://doi.org/10.3390/cancers13163927 - 04 Aug 2021
Cited by 23 | Viewed by 4570
Abstract
Colorectal cancer (CRC) mortality is mainly caused by patient refractoriness to common anti-cancer therapies and consequent metastasis formation. Besides, the notorious toxic side effects of chemotherapy are a concurrent obstacle to be tackled. Thus, new treatment approaches are needed to effectively improve patient [...] Read more.
Colorectal cancer (CRC) mortality is mainly caused by patient refractoriness to common anti-cancer therapies and consequent metastasis formation. Besides, the notorious toxic side effects of chemotherapy are a concurrent obstacle to be tackled. Thus, new treatment approaches are needed to effectively improve patient outcomes. Compelling evidence demonstrated that cancer stem cells (CSCs) are responsible for treatment failure and relapse. New natural treatment approaches showed capabilities to selectively target the CSC subpopulation by rendering them targetable by standard cytotoxic compounds. Herein we show the anti-cancer properties of the polymethoxyflavones and prenylflavonoids extracted from Citrus sinensis and Humulus lupulus, respectively. The natural biofunctional fractions, singularly and in combination, reduced the cell viability of CRC stem cells (CR-CSCs) and synergized with 5-fluorouracil and oxaliplatin (FOX) chemotherapy. These phenomena were accompanied by a reduced S and G2/M phase of the cell cycle and upregulation of cell death-related genes. Notably, both phytoextracts in combination with FOX thwarted stemness features in CR-CSCs as demonstrated by the impaired clonogenic potential and decreased Wnt pathway activation. Extracts lowered the expression of CD44v6 and affected the expansion of metastatic CR-CSCs in patients refractory to chemotherapy. Together, this study highlights the importance of polymethoxyflavones and prenylflavonoids as natural remedies to aid oncological therapies. Full article
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17 pages, 627 KiB  
Protocol
Organ Sparing for Locally Advanced Rectal Cancer after Neoadjuvant Treatment Followed by Electrochemotherapy
by Daniela Rega, Vincenza Granata, Antonella Petrillo, Ugo Pace, Cinzia Sassaroli, Massimiliano Di Marzo, Carmela Cervone, Roberta Fusco, Valeria D’Alessio, Guglielmo Nasti, Carmela Romano, Antonio Avallone, Biagio Pecori, Gerardo Botti, Fabiana Tatangelo, Piera Maiolino and Paolo Delrio
Cancers 2021, 13(13), 3199; https://doi.org/10.3390/cancers13133199 - 26 Jun 2021
Cited by 8 | Viewed by 1909
Abstract
Background: Currently, 45–55% of rectal cancer patients receive preoperative chemo- radio-therapy for Locally Advanced Rectal Cancer (LARC). The idea of our study is to use Electrochemotherapy (ECT) before surgery, in patients with major clinical response after neoadjuvant therapy, to allow for a more [...] Read more.
Background: Currently, 45–55% of rectal cancer patients receive preoperative chemo- radio-therapy for Locally Advanced Rectal Cancer (LARC). The idea of our study is to use Electrochemotherapy (ECT) before surgery, in patients with major clinical response after neoadjuvant therapy, to allow for a more conservative surgical approach. Objective: To evaluate the increase of the complete response rate after neoadjuvant treatment in LARC and to spare organ function due to total mesorectal excision (TME). Patients and Methods: This is a Phase II randomized controlled trial enrolling 70 patients that will be developed in two stages. In the first step, 28 patients will be enrolled: 14 of these will receive ECT for four weeks after neo-adjuvant treatment and then local excision (treatment group) and 14 patients will receive neo-adjuvant treatment and then local excision (control group). If an increase of response rate is observed in the first stage, and/or feasibility/safety is demonstrated, the second stage of the trial will be performed, enrolling an additional 42 patients. The treatment response. in both the control arm and the treatment arm, will be assessed using the histopathological tumor regression grade on tissue specimens after local excision. Full article
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22 pages, 1504 KiB  
Review
Liver Immune Microenvironment and Metastasis from Colorectal Cancer-Pathogenesis and Therapeutic Perspectives
by Xuezhen Zeng, Simon E. Ward, Jingying Zhou and Alfred S. L. Cheng
Cancers 2021, 13(10), 2418; https://doi.org/10.3390/cancers13102418 - 17 May 2021
Cited by 37 | Viewed by 4742
Abstract
A drastic difference exists between the 5-year survival rates of colorectal cancer patients with localized cancer and distal organ metastasis. The liver is the most favorable organ for cancer metastases from the colorectum. Beyond the liver-colon anatomic relationship, emerging evidence highlights the impact [...] Read more.
A drastic difference exists between the 5-year survival rates of colorectal cancer patients with localized cancer and distal organ metastasis. The liver is the most favorable organ for cancer metastases from the colorectum. Beyond the liver-colon anatomic relationship, emerging evidence highlights the impact of liver immune microenvironment on colorectal liver metastasis. Prior to cancer cell dissemination, hepatocytes secrete multiple factors to recruit or activate immune cells and stromal cells in the liver to form a favorable premetastatic niche. The liver-resident cells including Kupffer cells, hepatic stellate cells, and liver-sinusoidal endothelial cells are co-opted by the recruited cells, such as myeloid-derived suppressor cells and tumor-associated macrophages, to establish an immunosuppressive liver microenvironment suitable for tumor cell colonization and outgrowth. Current treatments including radical surgery, systemic therapy, and localized therapy have only achieved good clinical outcomes in a minority of colorectal cancer patients with liver metastasis, which is further hampered by high recurrence rate. Better understanding of the mechanisms governing the metastasis-prone liver immune microenvironment should open new immuno-oncology avenues for liver metastasis intervention. Full article
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23 pages, 3136 KiB  
Review
A Review of Colorectal Cancer in Terms of Epidemiology, Risk Factors, Development, Symptoms and Diagnosis
by Tomasz Sawicki, Monika Ruszkowska, Anna Danielewicz, Ewa Niedźwiedzka, Tomasz Arłukowicz and Katarzyna E. Przybyłowicz
Cancers 2021, 13(9), 2025; https://doi.org/10.3390/cancers13092025 - 22 Apr 2021
Cited by 289 | Viewed by 42376
Abstract
This review article contains a concise consideration of genetic and environmental risk factors for colorectal cancer. Known risk factors associated with colorectal cancer include familial and hereditary factors and lifestyle-related and ecological factors. Lifestyle factors are significant because of the potential for improving [...] Read more.
This review article contains a concise consideration of genetic and environmental risk factors for colorectal cancer. Known risk factors associated with colorectal cancer include familial and hereditary factors and lifestyle-related and ecological factors. Lifestyle factors are significant because of the potential for improving our understanding of the disease. Physical inactivity, obesity, smoking and alcohol consumption can also be addressed through therapeutic interventions. We also made efforts to systematize available literature and data on epidemiology, diagnosis, type and nature of symptoms and disease stages. Further study of colorectal cancer and progress made globally is crucial to inform future strategies in controlling the disease’s burden through population-based preventative initiatives. Full article
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16 pages, 4040 KiB  
Article
Remodeling of Cancer-Specific Metabolism under Hypoxia with Lactate Calcium Salt in Human Colorectal Cancer Cells
by Keun-Yeong Jeong, Jae-Jun Sim, Min Hee Park and Hwan Mook Kim
Cancers 2021, 13(7), 1518; https://doi.org/10.3390/cancers13071518 - 25 Mar 2021
Cited by 4 | Viewed by 3032
Abstract
Hypoxic cancer cells meet their growing energy requirements by upregulating glycolysis, resulting in increased glucose consumption and lactate production. Herein, we used a unique approach to change in anaerobic glycolysis of cancer cells by lactate calcium salt (CaLac). Human colorectal cancer (CRC) cells [...] Read more.
Hypoxic cancer cells meet their growing energy requirements by upregulating glycolysis, resulting in increased glucose consumption and lactate production. Herein, we used a unique approach to change in anaerobic glycolysis of cancer cells by lactate calcium salt (CaLac). Human colorectal cancer (CRC) cells were used for the study. Intracellular calcium and lactate influx was confirmed following 2.5 mM CaLac treatment. The enzymatic activation of lactate dehydrogenase B (LDHB) and pyruvate dehydrogenase (PDH) through substrate reaction of CaLac was investigated. Changes in the intermediates of the tricarboxylic acid (TCA) cycle were confirmed. The cell viability assay, tube formation, and wound-healing assay were performed as well as the confirmation of the expression of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF). In vivo antitumor effects were evaluated using heterotopic and metastatic xenograft animal models with 20 mg/kg CaLac administration. Intracellular calcium and lactate levels were increased following CaLac treatment in CRC cells under hypoxia. Then, enzymatic activation of LDHB and PDH were increased. Upon PDH knockdown, α-ketoglutarate levels were similar between CaLac-treated and untreated cells, indicating that TCA cycle restoration was dependent on CaLac-mediated LDHB and PDH reactivation. CaLac-mediated remodeling of cancer-specific anaerobic glycolysis induced destabilization of HIF-1α and a decrease in VEGF expression, leading to the inhibition of the migration of CRC cells. The significant inhibition of CRC growth and liver metastasis by CaLac administration was confirmed. Our study highlights the potential utility of CaLac supplementation in CRC patients who display reduced therapeutic responses to conventional modes owing to the hypoxic tumor microenvironment. Full article
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8 pages, 772 KiB  
Commentary
Therapeutic Implications of the Immunoscore in Patients with Colorectal Cancer
by Carine El Sissy, Amos Kirilovsky, Guy Zeitoun, Florence Marliot, Nacilla Haicheur, Christine Lagorce-Pagès, Jérôme Galon and Franck Pagès
Cancers 2021, 13(6), 1281; https://doi.org/10.3390/cancers13061281 - 13 Mar 2021
Cited by 12 | Viewed by 3740
Abstract
Four decades were needed to progress from the first demonstration of the independent prognostic value of lymphocytes infiltration in rectal cancers to the first recommendation from the international guidelines for the use of a standardized immune assay, namely the “Immunoscore” (IS), to accurately [...] Read more.
Four decades were needed to progress from the first demonstration of the independent prognostic value of lymphocytes infiltration in rectal cancers to the first recommendation from the international guidelines for the use of a standardized immune assay, namely the “Immunoscore” (IS), to accurately prognosticate colon cancers beyond the TNM-system. The standardization process included not only the IS conceptualization, development, fine-tuning, and validation by a large international consortium, but also a demonstration of the robustness and reproducibility across the world and testing of international norms and their effects on the IS. This is the first step of a major change of paradigm that now perceives cancer as the result of contradicting driving forces, i.e., the tumor expansion and the immune response, interacting dynamically and influencing the prognosis and the response to therapies. This prompted us to evaluate and evidence the capacity of the tumor immune status, as reflected by the IS, to accurately predict chemotherapy responses in an international, randomized cohort study of colon cancer. Moreover, we developed a derived IS performed on initial diagnostic biopsies (ISB) to assess response levels to neoadjuvant therapies. In rectal cancer, ISB was positively correlated with the degree of histologic response to neoadjuvant chemoradiotherapy and identified - alone and even more accurately if combined with clinical data- patients eligible for a noninvasive strategy. Based on these results, we are currently setting up an international cohort for confirmation. The potential role of IS with immunotherapies must be anticipated. Full article
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17 pages, 2061 KiB  
Review
Non-Steroidal Anti-Inflammatory Drugs in Colorectal Cancer Chemoprevention
by Jadwiga Maniewska and Dagmara Jeżewska
Cancers 2021, 13(4), 594; https://doi.org/10.3390/cancers13040594 - 03 Feb 2021
Cited by 40 | Viewed by 4946
Abstract
Since colorectal cancer is one of the world’s most common cancers, studies on its prevention and early diagnosis are an emerging area of clinical oncology these days. For this study, a review of randomized controlled, double-blind clinical trials of selected NSAIDs (aspirin, sulindac [...] Read more.
Since colorectal cancer is one of the world’s most common cancers, studies on its prevention and early diagnosis are an emerging area of clinical oncology these days. For this study, a review of randomized controlled, double-blind clinical trials of selected NSAIDs (aspirin, sulindac and celecoxib) in chemoprevention of colorectal cancer was conducted. The main molecular anticancer activity of NSAIDs is thought to be a suppression of prostaglandin E2 synthesis via cyclooxygenase-2 inhibition, which causes a decrease in tumor cell proliferation, angiogenesis, and increases apoptosis. The lower incidence of colorectal cancer in the NSAID patients suggests the long-lasting chemopreventive effect of drugs studied. This new approach to therapy of colorectal cancer may transform the disease from a terminal to a chronic one that can be taken under control. Full article
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