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Cancers
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Colorectal Cancer: Tumour Microenvironment, Cellular Heterogeneity and Therapeutics
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Colorectal Cancer: Tumour Microenvironment, Cellular Heterogeneity and Therapeutics

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 18760

Special Issue Editor

Prof. Dr. Abdolrahman Shams Nateri

E-Mail Website
Guest Editor
Cancer Genetics & Stem Cell Group, Division of Cancer & Stem Cells, School of Medicine, University of Nottingham BioDiscovery Institute, Room B207C, Nottingham, UK
Interests: Cancer genetics; Signaling; Stem cells; Cell fate determination; Cancer models; Tumour microenvironment; Molecular basis of metastasis; Multi-omics; Molecular therapies

Special Issue Information

Dear Colleagues,

Colorectal cancer is a leading cause of cancer death worldwide. During the progression of colorectal tumours, neoplastic cells transmit a series of signals that modify the adjacent microenvironment and involves several feedback loops of both activating and inhibiting paths between different cells. This heterocellular communication between tumour epithelium and the stromal cells facilitates the emergence of complex phenotypes through reciprocal and dynamic interaction, which leads to heterogeneous drug response.

The primary focus of this Special Issue is to address the transcriptomics, proteomics, and metabolomics alterations involved in tumour microenvironments, cell-cell communication, tumour dissemination, and therapies. Development and validation of the advanced mono-cellular and multicellular models to measure and validate the identified pathways are of particular interests.

Prof. Dr. Abdolrahman Shams Nateri
Guest Editor

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

  • Colorectal cancer
  • intestinal/ colon cancer models
  • tumour microenvironment
  • cell-cell communication signals
  • metastasis
  • multi-omics technologies
  • molecular therapies

Published Papers (7 papers)

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Research

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21 pages, 5827 KiB  
Article
Metformin Treatment Reduces CRC Aggressiveness in a Glucose-Independent Manner: An In Vitro and Ex Vivo Study
by Marie Boutaud, Clément Auger, Mireille Verdier and Niki Christou
Cancers 2023, 15(14), 3724; https://doi.org/10.3390/cancers15143724 - 22 Jul 2023
Cited by 1 | Viewed by 1010
Abstract
(1) Background: Metformin, an anti-diabetic drug, seems to protect against aggressive acquisition in colorectal cancers (CRCs). However, its mechanisms are still really unknown, raising questions about the possibility of its positive impact on non-diabetic patients with CRC. (2) Methods: An in vitro study [...] Read more.
(1) Background: Metformin, an anti-diabetic drug, seems to protect against aggressive acquisition in colorectal cancers (CRCs). However, its mechanisms are still really unknown, raising questions about the possibility of its positive impact on non-diabetic patients with CRC. (2) Methods: An in vitro study based on human colon cancer cell lines and an ex vivo study with different colon cancer stages with proteomic and transcriptomic analyses were initiated. (3) Results: Metformin seems to protect from colon cancer invasive acquisition, irrespective of glucose concentration. (4) Conclusions: Metformin could be used as an adjuvant treatment to surgery for both diabetic and non-diabetic patients in order to prevent the acquisition of aggressiveness and, ultimately, recurrences. Full article
(This article belongs to the Special Issue Colorectal Cancer: Tumour Microenvironment, Cellular Heterogeneity and Therapeutics)
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10 pages, 260 KiB  
Article
Comorbidities and Risk Factors of Patients Diagnosed with CRC after Positive Fecal Test in Real Life
by Naim Abu-Freha, Rachel Gouldner, Bracha Cohen, Michal Gordon, Orly Sagi, Gadeer Taha, Liza Ben Shoshan and Zohar Levi
Cancers 2022, 14(22), 5557; https://doi.org/10.3390/cancers14225557 - 12 Nov 2022
Viewed by 1151
Abstract
(1) Background: Fecal occult blood test (FOBT) is the modality of choice in most countries for colorectal cancer (CRC) screening. We aimed to investigate the risk factors for CRC among patients with a positive FOBT in real life. (2) Methods: This was a [...] Read more.
(1) Background: Fecal occult blood test (FOBT) is the modality of choice in most countries for colorectal cancer (CRC) screening. We aimed to investigate the risk factors for CRC among patients with a positive FOBT in real life. (2) Methods: This was a retrospective study that included patients who tested positive for FOBT. Data regarding the comorbidities and laboratories were collected and compared between CRC and non-CRC groups. (3) Results: Positive FOBT was found among 45,500 (5.36%) subjects and CRC was found in 1502 (3.3%). CRC patients were older, age 62.7 ± 7.15 years compared with 59.33 ± 7.3 years (p < 0.001), and had significantly higher rates of hypertension (48.4% vs. 44.7%, p = 0.002), iron-deficiency anemia (20.6% vs. 16.4, p < 0.001), family history of CRC (7.3% vs. 5.1%, p < 0.001), and previous CRC (6.5% vs. 0.3%, p < 0.001). Lower levels of hemoglobin, iron, and ferritin were found in the CRC group. Age, family history of CRC, and previous CRC were found to be significant risk factors for diagnosis of CRC after positive FOBT with OR of 1.057, 1.4, and 15.9, respectively. (4) Conclusions: Iron-deficiency anemia, family history of CRC, previous colorectal cancer, and low hemoglobin, iron, and ferritin levels should direct physicians to give high priority to colonoscopy scheduling. Full article
(This article belongs to the Special Issue Colorectal Cancer: Tumour Microenvironment, Cellular Heterogeneity and Therapeutics)
17 pages, 1803 KiB  
Article
Aflibercept Plus FOLFIRI as Second-Line Treatment for Metastatic Colorectal Cancer: A Single-Institution Real-Life Experience
by Daniele Lavacchi, Giandomenico Roviello, Elisa Giommoni, Lorenzo Dreoni, Silvia Derio, Marco Brugia, Amedeo Amedei, Serena Pillozzi and Lorenzo Antonuzzo
Cancers 2021, 13(15), 3863; https://doi.org/10.3390/cancers13153863 - 31 Jul 2021
Cited by 6 | Viewed by 2221
Abstract
The addition of aflibercept to FOLFIRI has been demonstrated to improve survival in patients with metastatic colorectal cancer (mCRC) who progressed after receiving a standard oxaliplatin-based regimen. In this retrospective, single-institution, observational study we collected clinical data from mCRC patients who received aflibercept [...] Read more.
The addition of aflibercept to FOLFIRI has been demonstrated to improve survival in patients with metastatic colorectal cancer (mCRC) who progressed after receiving a standard oxaliplatin-based regimen. In this retrospective, single-institution, observational study we collected clinical data from mCRC patients who received aflibercept in combination with FOLFIRI in routine clinical practice from October 2012 to March 2021 to describe feasibility and efficacy of this regimen in a real-world population. Forty-nine patients receiving aflibercept-FOLFIRI as second-line treatment were identified, 40.8% of whom were aged over 65 years. The majority of patients had multi-organ metastases (73.5%), and had previously received bevacizumab in combination with chemotherapy (CT) as first-line treatment (79.6%). Median overall survival (OS) and progression-free survival (PFS) were 13 and 6 months, respectively; overall response rate (ORR) and disease control rate (DCR) were 12.3% and 49.1%, respectively. Several factors were associated with survival in univariate analysis, including PFS in first-line therapy, number of metastatic sites, bone metastases and others. However, in multivariate analysis, only PFS in first-line CT over 12 months was significantly associated with better OS (HR 0.32; 95% CI 0.13–0.79; p = 0.01). Hypertension was the most commonly reported grade (G) 3–4 adverse event (AE), affecting 18.4% of the overall population. Thromboembolic events were observed in 16.3% of patients, hemorrhagic events in 10.2%, and proteinuria in 8.2%. Neutropenia was the most frequently observed hematological G3–4 AE with an incidence of 10.2%. Aflibercept-FOLFIRI has been confirmed as a feasible second-line treatment for mCRC in a re-al-life setting, and PFS in first-line therapy >12 months resulted as the only predictive marker of better survival. Full article
(This article belongs to the Special Issue Colorectal Cancer: Tumour Microenvironment, Cellular Heterogeneity and Therapeutics)
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19 pages, 8312 KiB  
Article
PIK3C3 Inhibition Promotes Sensitivity to Colon Cancer Therapy by Inhibiting Cancer Stem Cells
by Balawant Kumar, Rizwan Ahmad, Swagat Sharma, Saiprasad Gowrikumar, Mark Primeaux, Sandeep Rana, Amarnath Natarajan, David Oupicky, Corey R. Hopkins, Punita Dhawan and Amar B. Singh
Cancers 2021, 13(9), 2168; https://doi.org/10.3390/cancers13092168 - 30 Apr 2021
Cited by 25 | Viewed by 4069
Abstract
Background: Despite recent advances in therapies, resistance to chemotherapy remains a critical problem in the clinical management of colorectal cancer (CRC). Cancer stem cells (CSCs) play a central role in therapy resistance. Thus, elimination of CSCs is crucial for effective CRC therapy; however, [...] Read more.
Background: Despite recent advances in therapies, resistance to chemotherapy remains a critical problem in the clinical management of colorectal cancer (CRC). Cancer stem cells (CSCs) play a central role in therapy resistance. Thus, elimination of CSCs is crucial for effective CRC therapy; however, such strategies are limited. Autophagy promotes resistance to cancer therapy; however, whether autophagy protects CSCs to promote resistance to CRC-therapy is not well understood. Moreover, specific and potent autophagy inhibitors are warranted as clinical trials with hydroxychloroquine have not been successful. Methods: Colon cancer cells and tumoroids were used. Fluorescent reporter-based analysis of autophagy flux, spheroid and side population (SP) culture, and qPCR were done. We synthesized 36-077, a potent inhibitor of PIK3C3/VPS34 kinase, to inhibit autophagy. Combination treatments were done using 5-fluorouracil (5-FU) and 36-077. Results: The 5-FU treatment induced autophagy only in a subset of the treated colon cancer. These autophagy-enriched cells also showed increased expression of CSC markers. Co-treatment with 36-077 significantly improved efficacy of the 5-FU treatment. Mechanistic studies revealed that combination therapy inhibited GSK-3β/Wnt/β-catenin signaling to inhibit CSC population. Conclusion: Autophagy promotes resistance to CRC-therapy by specifically promoting GSK-3β/Wnt/β-catenin signaling to promote CSC survival, and 36-077, a PIK3C3/VPS34 inhibitor, helps promote efficacy of CRC therapy. Full article
(This article belongs to the Special Issue Colorectal Cancer: Tumour Microenvironment, Cellular Heterogeneity and Therapeutics)
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Review

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28 pages, 1914 KiB  
Review
Implication of Obesity and Gut Microbiome Dysbiosis in the Etiology of Colorectal Cancer
by Samradhi Singh, Poonam Sharma, Devojit Kumar Sarma, Manoj Kumawat, Rajnarayan Tiwari, Vinod Verma, Ravinder Nagpal and Manoj Kumar
Cancers 2023, 15(6), 1913; https://doi.org/10.3390/cancers15061913 - 22 Mar 2023
Cited by 9 | Viewed by 3628
Abstract
The complexity and variety of gut microbiomes within and among individuals have been extensively studied in recent years in connection to human health and diseases. Our growing understanding of the bidirectional communication between metabolic diseases and the gut microbiome has also highlighted the [...] Read more.
The complexity and variety of gut microbiomes within and among individuals have been extensively studied in recent years in connection to human health and diseases. Our growing understanding of the bidirectional communication between metabolic diseases and the gut microbiome has also highlighted the significance of gut microbiome dysbiosis in the genesis and development of obesity-related cancers. Therefore, it is crucial to comprehend the possible role of the gut microbiota in the crosstalk between obesity and colorectal cancer (CRC). Through the induction of gut microbial dysbiosis, gut epithelial barrier impairment, metabolomic dysregulation, chronic inflammation, or dysregulation in energy harvesting, obesity may promote the development of colorectal tumors. It is well known that strategies for cancer prevention and treatment are most effective when combined with a healthy diet, physical activity, and active lifestyle choices. Recent studies also suggest that an improved understanding of the complex linkages between the gut microbiome and various cancers as well as metabolic diseases can potentially improve cancer treatments and overall outcomes. In this context, we herein review and summarize the clinical and experimental evidence supporting the functional role of the gut microbiome in the pathogenesis and progression of CRC concerning obesity and its metabolic correlates, which may pave the way for the development of novel prognostic tools for CRC prevention. Therapeutic approaches for restoring the microbiome homeostasis in conjunction with cancer treatments are also discussed herein. Full article
(This article belongs to the Special Issue Colorectal Cancer: Tumour Microenvironment, Cellular Heterogeneity and Therapeutics)
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23 pages, 1079 KiB  
Review
Microenvironmental Reactive Oxygen Species in Colorectal Cancer: Involved Processes and Therapeutic Opportunities
by Maria Alba Sorolla, Ivan Hidalgo, Anabel Sorolla, Robert Montal, Ona Pallisé, Antonieta Salud and Eva Parisi
Cancers 2021, 13(20), 5037; https://doi.org/10.3390/cancers13205037 - 09 Oct 2021
Cited by 22 | Viewed by 3040
Abstract
Colorectal cancer (CRC) is the fourth most common cause of cancer deaths worldwide. Although screening programs have reduced mortality rates, there is a need for research focused on finding the main factors that lead primary CRC to progress and metastasize. During tumor progression, [...] Read more.
Colorectal cancer (CRC) is the fourth most common cause of cancer deaths worldwide. Although screening programs have reduced mortality rates, there is a need for research focused on finding the main factors that lead primary CRC to progress and metastasize. During tumor progression, malignant cells modify their habitat, corrupting or transforming cells of different origins and creating the tumor microenvironment (TME). Cells forming the TME like macrophages, neutrophils, and fibroblasts generate reactive oxygen species (ROS) that modify the cancer niche. The effects of ROS in cancer are very diverse: they promote cellular proliferation, epithelial-to-mesenchymal transition (EMT), evasion of cell death programs, migration, and angiogenesis. Due to the multifaceted role of ROS in cancer cell survival and function, ROS-modulating agents such as antioxidants or pro-oxidants could have therapeutic potential in cancer prevention and/or as a complement to systemic treatments. In this review, we will examine the main ROS producer cells and their effects on cancer progression and metastasis. Furthermore, we will enumerate the latest clinical trials where pro-oxidants and antioxidants have therapeutic uses in CRC. Full article
(This article belongs to the Special Issue Colorectal Cancer: Tumour Microenvironment, Cellular Heterogeneity and Therapeutics)
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Other

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11 pages, 1000 KiB  
Perspective
Could Microplastics Be a Driver for Early Onset Colorectal Cancer?
by Shelley Li, Jacqueline I. Keenan, Ian C. Shaw and Frank A. Frizelle
Cancers 2023, 15(13), 3323; https://doi.org/10.3390/cancers15133323 - 24 Jun 2023
Cited by 4 | Viewed by 2963
Abstract
Introduction: The incidence of colorectal cancer in those under 50 years of age (early onset colorectal cancer (EOCRC)) is increasing throughout the world. This has predominantly been an increase in distal colonic and rectal cancers, which are biologically similar to late onset colorectal [...] Read more.
Introduction: The incidence of colorectal cancer in those under 50 years of age (early onset colorectal cancer (EOCRC)) is increasing throughout the world. This has predominantly been an increase in distal colonic and rectal cancers, which are biologically similar to late onset colorectal cancer (LOCRC) but with higher rates of mucinous or signet ring histology, or poorly differentiated cancers. The epidemiology of this change suggests that it is a cohort effect since 1960, and is most likely driven by an environmental cause. We explore the possible role of microplastics as a driver for this change. Review: The development of sporadic colorectal cancer is likely facilitated by the interaction of gut bacteria and the intestinal wall. Normally, a complex layer of luminal mucus provides colonocytes with a level of protection from the effects of these bacteria and their toxins. Plastics were first developed in the early 1900s. After 1945 they became more widely used, with a resultant dramatic increase in plastic pollution and their breakdown to microplastics. Microplastics (MPs) are consumed by humans from an early age and in increasingly large quantities. As MPs pass through the gastrointestinal tract they interact with the normal physiological mechanism of the body, particularly in the colon and rectum, where they may interact with the protective colonic mucus layer. We describe several possible mechanisms of how microplastics may disrupt this mucus layer, thus reducing its protective effect and increasing the likelihood of colorectal cancer. Conclusions: The epidemiology of increase in EOCRC suggests an environmental driver. This increase in EOCRC matches the time sequence in which we could expect to see an effect of rapid increase of MPs in the environment and, as such, we have explored possible mechanisms for this effect. We suggest that it is possible that the MPs damage the barrier integrity of the colonic mucus layer, thus reducing its protective effect. MPs in CRC pathogenesis warrants further investigation. Future directions: Further clarification needs to be sought regarding the interaction between MPs, gut microbiota and the mucus layer. This will need to be modelled in long-term animal studies to better understand how chronic consumption of environmentally-acquired MPs may contribute to an increased risk of colorectal carcinogenesis. Full article
(This article belongs to the Special Issue Colorectal Cancer: Tumour Microenvironment, Cellular Heterogeneity and Therapeutics)
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