INFLAMMATION AND COLON CANCER. MOLECULAR AND IMMUNOLOGICAL MECHANISMS

After the analysis of data presented in the international literature there are still a lot of controversial issues on the impact of inflammation on the development of colon cancer. Molecular mechanisms of various types of colorectal cancer are different and connected with inflammatory bowel diseases. There are some immunological similarities and differences between colitis-associated colon cancer occurring in inflammation and other types of colorectal cancer developing without any signs of inflammatory process. The gut microbiota significantly influences on the development of sporadic colorectal cancer and colitis-associated cancer. Malignant colon tumors, without dependence on the colorectal cancer type, have an increased expression of pro-inflammatory cytokines. The role of tumor-infiltrating immunocytes and tumor inflammatory microenvironment in colorectal cancer is complex: they are involved in antitumor immune defense and play a pro-oncogenic role. In perspective anti-inflammatory biologic drugs are expected to decrease the risk of the development of colorectal cancer.

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Cyst(e)ine in nutrition formulation promotes colon cancer growth and chemoresistance by activating mTORC1 and scavenging ROS

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00581-9 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Jiao Wu ◽

Sai-Ching Jim Yeung ◽

Sicheng Liu ◽

Aiham Qdaisat ◽

Dewei Jiang ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Weight Loss ◽

Cancer Patients ◽

Cancer Cell ◽

Cancer Progression ◽

Colorectal Cancer Patient ◽

Nutrition Support ◽

Immunodeficient Mice ◽

The Impact

AbstractWeight loss and cachexia are common problems in colorectal cancer patients; thus, parenteral and enteral nutrition support play important roles in cancer care. However, the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied. In this study, we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival (P < 0.001) than those who did not. Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice, predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis, resulting in mTORC1 activation. mTORC1 inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation. In addition, cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione. We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin. These findings indicate that cyst(e)ine, as part of supplemental nutrition, plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.

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Clinical Importance of Wnt5a in the Pathogenesis of Colorectal Cancer

Journal of Oncology ◽

10.1155/2021/3136508 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Mehran Pashirzad ◽

Thozhukat Sathyapalan ◽

Amirhossein Sahebkar

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Potential Role ◽

Clinical Importance ◽

Signaling Cascades ◽

Cancer Type ◽

Invasion And Metastasis ◽

Cellular Processes ◽

Wnt5a Expression ◽

Noncanonical Signaling

Wnt5a is one of the potent signaling molecules that initiates responses involved in cancer through activation of both canonical and noncanonical signaling cascades. Wnt5a both directly and indirectly triggers cancer-associated signaling pathways based on the cancer type. In colorectal cancer (CRC), altering Wnt5a expression can influence several cellular processes of tumor cells, including proliferation, differentiation, migration, invasion, and metastasis. This review summarizes the molecular mechanisms and clinical importance of Wnt5a in the pathogenesis of CRC for better understanding the pathogenesis and its potential role as a prognostic marker and as an appropriate therapeutic target in the treatment of this disease in the future.

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Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant

Cell Death and Disease ◽

10.1038/s41419-020-03232-z ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Michael Fichtner ◽

Emir Bozkurt ◽

Manuela Salvucci ◽

Christopher McCann ◽

Katherine A. McAllister ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Molecular Mechanisms ◽

Mononuclear Cells ◽

Caspase 8 ◽

Colon Cancer Cells ◽

Apoptosis Pathway ◽

Iap Antagonist

AbstractColorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic chemotherapy in the adjuvant or palliative setting vary greatly between patients, and colorectal cancer cells often resist chemotherapy by evading apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by inhibition of XIAP. Due to the multiple molecular mechanisms-of-action of these targets, responses to IAP antagonist may differ between molecularly distinct colon cancer cells. In this study, responses to the IAP antagonist Birinapant and oxaliplatin/5-fluorouracil (5-FU) were investigated in 14 colon cancer cell lines, representing the consensus molecular subtypes (CMS). Treatment with Birinapant alone did not result in a substantial increase in apoptotic cells in this cell line panel. Annexin-V/PI assays quantified by flow cytometry and high-content screening showed that Birinapant increased responses of CMS1 and partially CMS3 cell lines to oxaliplatin/5-FU, whereas CMS2 cells were not effectively sensitized. FRET-based imaging of caspase-8 and -3 activation validated these differences at the single-cell level, with CMS1 cells displaying sustained activation of caspase-8-like activity during Birinapant and oxaliplatin/5-FU co-treatment, ultimately activating the intrinsic mitochondrial apoptosis pathway. In CMS2 cell lines, Birinapant exhibited synergistic effects in combination with TNFα, suggesting that Birinapant can restore extrinsic apoptosis signaling in the context of inflammatory signals in this subtype. To explore this further, we co-cultured CMS2 and CMS1 colon cancer cells with peripheral blood mononuclear cells. We observed increased cell death during Birinapant single treatment in these co-cultures, which was abrogated by anti-TNFα-neutralizing antibodies. Collectively, our study demonstrates that IAP inhibition is a promising modulator of response to oxaliplatin/5-FU in colorectal cancers of the CMS1 subtype, and may show promise as in the CMS2 subtype, suggesting that molecular subtyping may aid as a patient stratification tool for IAP antagonists in this disease.

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miR-224 targets BTRC and promotes cell migration and invasion in colorectal cancer

3 Biotech ◽

10.1007/s13205-020-02477-x ◽

2020 ◽

Vol 10 (11) ◽

Author(s):

Qi Zheng ◽

Jane J. Yu ◽

Chenggang Li ◽

Jiali Li ◽

Jiping Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Migration ◽

Protein Expression ◽

Molecular Mechanisms ◽

Early Stage ◽

Luciferase Assay ◽

Migration And Invasion ◽

Cell Migration And Invasion ◽

Normal Tissues ◽

The Impact

AbstractOur study aims to investigate the impact of miR-224 on cell migration and invasion in colorectal cancer (CRC) as well as its molecular mechanisms. The results showed that miR-224 was significantly upregulated in CRC compared to normal tissues via the TCGA database. Overexpression of miR-224 promoted CRC cell migration and invasion, while inhibition of miR-224 demonstrated the opposite result via transwell assays. In addition, we found that BTRC was a target gene of miR-224 through the miRecords database and dual-luciferase assay, while western blot together with RT-qPCR showed that inhibition of miR-224 led to elevated BTRC expression in protein level but not in mRNA level, and also decreased the expression of β-catenin. In reference to the Human Protein Atlas, BTRC protein expression was higher in normal tissues than in CRC tissues. In conclusion, miR-224 regulates its target BTRC protein expression and its related Wnt/β-catenin pathway. Its impact on cell migration and invasion in CRC cells suggested that miR-224 could be a prospective therapeutic target for early-stage non-metastatic CRC.

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The Impact of Diet on the Involvement of Non-Coding RNAs, Extracellular Vesicles, and Gut Microbiome-Virome in Colorectal Cancer Initiation and Progression

Frontiers in Oncology ◽

10.3389/fonc.2020.583372 ◽

2020 ◽

Vol 10 ◽

Author(s):

Bene A. Ekine-Afolabi ◽

Anoka A. Njan ◽

Solomon O. Rotimi ◽

Anu R. I. ◽

Attia M. Elbehi ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Dna Methyltransferase ◽

Molecular Mechanisms ◽

Cell Communication ◽

Extracellular Vesicle ◽

Dietary Factors ◽

Tumor Onset ◽

Non Coding Rnas ◽

The Impact

Cancer is the major cause of morbidity and mortality in the world today. The third most common cancer and which is most diet related is colorectal cancer (CRC). Although there is complexity and limited understanding in the link between diet and CRC, the advancement in research methods have demonstrated the involvement of non-coding RNAs (ncRNAs) as key regulators of gene expression. MicroRNAs (miRNAs) which are a class of ncRNAs are key players in cancer related pathways in the context of dietary modulation. The involvement of ncRNA in cancer progression has recently been clarified throughout the last decade. ncRNAs are involved in biological processes relating to tumor onset and progression. The advances in research have given insights into cell to cell communication, by highlighting the pivotal involvement of extracellular vesicle (EV) associated-ncRNAs in tumorigenesis. The abundance and stability of EV associated ncRNAs act as a new diagnostic and therapeutic target for cancer. The understanding of the deranging of these molecules in cancer can give access to modulating the expression of the ncRNAs, thereby influencing the cancer phenotype. Food derived exosomes/vesicles (FDE) are gaining interest in the implication of exosomes in cell-cell communication with little or no understanding to date on the role FDE plays. There are resident microbiota in the colon; to which the imbalance in the normal intestinal occurrence leads to chronic inflammation and the production of carcinogenic metabolites that lead to neoplasm. Limited studies have shown the implication of various types of microbiome in CRC incidence, without particular emphasis on fungi and protozoa. This review discusses important dietary factors in relation to the expression of EV-associated ncRNAs in CRC, the impact of diet on the colon ecosystem with particular emphasis on molecular mechanisms of interactions in the ecosystem, the influence of homeostasis regulators such as glutathione, and its conjugating enzyme-glutathione S-transferase (GST) polymorphism on intestinal ecosystem, oxidative stress response, and its relationship to DNA adduct fighting enzyme-0-6-methylguanine-DNA methyltransferase. The understanding of the molecular mechanisms and interaction in the intestinal ecosystem will inform on the diagnostic, preventive and prognosis as well as treatment of CRC.

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Microsatellite instability status differentially associates with intratumoral immune microenvironment in human cancers

Briefings in Bioinformatics ◽

10.1093/bib/bbaa180 ◽

2020 ◽

Author(s):

Peng Zhang ◽

Mingyue Liu ◽

Ya Cui ◽

Pan Zheng ◽

Yang Liu

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Therapeutic Response ◽

In Silico Analysis ◽

Cancer Type ◽

Clinical Responses ◽

Stomach Adenocarcinoma ◽

Immune Contexture ◽

Cancer Types ◽

The Impact

Abstract Based on clinical outcomes in colorectal cancer, high microsatellite instability (MSI-H) has recently been approved by the Food and Drug Administration (FDA) as a genetic test to select patients for immunotherapy targeting PD-1 and/or CTLA-4 without limitation to cancer type. However, it is unclear whether the MSI-H would broadly alter the tumor microenvironment to confer the therapeutic response of different cancer types to immunotherapy. To fill in this gap, we performed an in silico analysis of tumor immunity among different MSI statuses in five cancer types. We found that consistent with clinical responses to immunotherapy, MSI-H and non-MSI-H samples from colorectal cancer (COAD-READ) exhibited distinct infiltration levels and immune phenotypes. Surprisingly, the immunological difference between MSI-H and non-MSI-H samples was diminished in stomach adenocarcinoma and esophageal carcinoma (STAD-ESCA) and completely disappeared in uterine corpus endometrial carcinoma (UCEC). Regardless of cancer types, the abundance of tumor-infiltrating immune cells, rather than MSI status, strongly associated with the clinical outcome. Since preexisting antitumor immune response in the tumor (hot cancer) is accepted as a prerequisite to the therapeutic response to anti-PD-1/CTLA-4 immunotherapy, our data demonstrate that the impact of MSI varied on immune contexture will lead to the further evaluation of predictive immunotherapy responsiveness based on the universal biomarker of MSI status.

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Cognitive impairment after cytotoxic chemotherapy

Neuro-Oncology Practice ◽

10.1093/nop/npz052 ◽

2019 ◽

Vol 7 (1) ◽

pp. 11-21 ◽

Cited By ~ 2

Author(s):

Petra Huehnchen ◽

Antonia van Kampen ◽

Wolfgang Boehmerle ◽

Matthias Endres

Keyword(s):

Breast Cancer ◽

Colon Cancer ◽

Cognitive Impairment ◽

Cancer Patients ◽

Cytotoxic Chemotherapy ◽

Cytotoxic Drugs ◽

Cytotoxic Agents ◽

Cancer Type ◽

Breast Cancer Patients ◽

The Impact

Abstract Background Neurotoxicity is a frequent side effect of cytotoxic chemotherapy and affects a large number of patients. Despite the high medical need, few research efforts have addressed the impact of cytotoxic agents on cognition (ie, postchemotherapy cognitive impairment; PCCI). One unsolved question is whether individual cytotoxic drugs have differential effects on cognition. We thus examine the current state of research regarding PCCI. Neurological symptoms after targeted therapies and immunotherapies are not part of this review. Methods A literature search was conducted in the PubMed database, and 1215 articles were reviewed for predefined inclusion and exclusion criteria. Thirty articles were included in the systematic review. Results Twenty-five of the included studies report significant cognitive impairment. Of these, 21 studies investigated patients with breast cancer. Patients mainly received combinations of 5-fluorouracil, epirubicin, cyclophosphamide, doxorubicin, and taxanes (FEC/FEC-T). Five studies found no significant cognitive impairment in chemotherapy patients. Of these, 2 studies investigated patients with colon cancer receiving 5-fluorouracil and oxaliplatin (FOLFOX). Independent risk factors for PCCI were patient age, mood alterations, cognitive reserve, and the presence of apolipoprotein E e4 alleles. Conclusions There is evidence that certain chemotherapy regimens cause PCCI more frequently than others as evidenced by 21 out of 23 studies in breast cancer patients (mainly FEC-T), whereas 2 out of 3 studies with colon cancer patients (FOLFOX) did not observe significant changes. Further studies are needed defining patient cohorts by treatment protocol in addition to cancer type to elucidate the effects of individual cytotoxic drugs on cognitive functions.

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Assessing the impact of a targeted educational initiative on colorectal cancer lymph node retrieval: A Fox Chase Cancer Center Partners' quality initiative

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.6524 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 6524-6524

Author(s):

B. Curley ◽

M. A. O'Grady ◽

S. Litwin ◽

K. Stitzenberg ◽

H. Armitage ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Lymph Node ◽

Lymph Nodes ◽

Cancer Center ◽

Community Hospitals ◽

Educational Initiative ◽

Tumor Boards ◽

Nodal Yield ◽

The Impact

6524 Background: The retrieval of ≥12 lymph nodes in a colorectal cancer surgical specimen is an established quality metric. The impact of targeted education to improve nodal yield at community hospitals has not been studied. We initiated an intensive educational program through the Fox Chase Cancer Center Partner (FCCCP) hospitals to improve nodal retrieval in colon cancer specimens. Methods: At 12 FCCCP community hospitals from 2004–05, educational initiatives were conducted by FCCC staff and included group presentations at hospital tumor boards, cancer and quality committees, and regional CME. Individual presentations to pathologists and surgeons were held. Tumor registry data were retrospectively collected from FCCCP from 2003 (pre-intervention) to 2006 (post-intervention) for patients undergoing curative colon cancer surgery. Data abstracted were age, sex, race, stage, surgical procedure, and total number of nodes examined. The primary end point was % surgical specimens with ≥12 lymph nodes. Obtaining at least 250 records per year would allow ≥90% power to detect a change from a baseline level of ∼40% to ≥50% after intervention. Results: Data from 4,208 patients from 12 FCCCP hospitals were collected. Overall characteristics: male/female (48%/52%), race (W 83%, AA 7%, other 10%), age (<50:6%, 50–70: 34%, >70:60%), node ± (39%/61%). The % of colon cancer operations with ≥12 nodes significantly increased over the four years of the study (Table, p<.00001). This difference persisted when pooling years before and after the intervention (2003–04 vs. 2005–06, p <0.0001). There was no difference in nodal yield between two pre-intervention years (2003 vs. 2004, p=0.1). No differences in other characteristics such as age, sex, race, or % lymph node positive were noted between years. Conclusions: A multi-intervention targeted educational initiative in a large community cancer network is feasible and associated with increased colon cancer nodal retrieval. [Table: see text] No significant financial relationships to disclose.

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Stage-based variation in the impact of colon cancer surveillance.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3609 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3609-3609

Author(s):

Lucy Gately ◽

Christine Semira ◽

Azim Jalali ◽

Ian Faragher ◽

Sumitra Ananda ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Recurrence Rate ◽

Cancer Surveillance ◽

Stage I ◽

Stage At Diagnosis ◽

Recurrence Rates ◽

Curative Intent ◽

Oligometastatic Disease ◽

The Impact

3609 Background: Multiple meta-analyses have demonstrated that routine surveillance following curative intent colorectal cancer surgery improves overall survival. This benefit is largely driven by early detection and curative intent resection of oligometastatic disease. Intuitively, any surveillance benefit should be proportional to recurrence risk, leading some to question the value of surveillance for stage I patients where recurrence rates are low. However, the survival benefit of surveillance has not previously been reported by stage. Methods: We explored data from a multi-site cohort of colorectal cancer patients (pts) diagnosed from 1 January 2001 to 31 December 2016. Pts were followed according to standard protocols with a standardized comprehensive outcome data captured prospectively. Pts with a rectal primary or metastatic disease at presentation were excluded from the analysis. We examined the correlation of stage at diagnosis with tumor recurrence and subsequent outcomes. Results: Of 3608 colon cancer pts, 690 (19%) had stage 1, 1580 (44%) had stage 2, and 1338 (37%) had stage 3 disease. Median follow-up was 7.8 years. Stage at diagnosis impacted recurrence rate (4% stage I vs 12% stage II vs 28% stage III, p < .0001) but not median time to recurrence. Recurrence patterns varied with stage (e.g. distant nodal disease 5% vs 7% vs 16%, p = .003; liver metastases 90% vs 53% vs 42%, p = 0.001). In pts with recurrence, resection of oligometastatic disease varied significantly by stage (58% vs 42% vs 30%, p < .0001) as did post-resection 5 year survival (91% vs 66% vs 43%, p < 0.001). In pts with recurrence treated with palliative intent, stage at diagnosis also impacted post-recurrence 5 year survival (11% vs 7% vs 5%, p < 0.03). Conclusions: Colon cancer stage at diagnosis substantially impacts the proportion of pts able to undergo curative intent surgery for surveillance detected recurrent disease, potentially driven by stage specific metastatic patterns. Stage at diagnosis also has a significant impact on post-resection survival outcomes potentially driven by stage specific biology. Our data indicate a far greater survival impact of surveillance for stage I colon cancer than would be anticipated based on recurrence rate alone.

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Andean Berry (Vaccinium meridionale Swartz) Juice in Combination With Aspirin Modulated Apoptotic Signaling in Colon Cancer In Vitro and In Vivo

Current Developments in Nutrition ◽

10.1093/cdn/nzab036_003 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 261-261

Author(s):

Sandra Arango-Varela ◽

Ivan Luzardo ◽

Maria Maldonado-Celis

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

In Silico ◽

Aberrant Crypt Foci ◽

Apoptotic Signaling ◽

Polyphenolic Composition ◽

Apoptotic Effects ◽

The Impact

Abstract Objectives This research aimed to assess the impact of Andean Berry (Vaccinium meridionale Swartz) juice (ABJ) in combination with Aspirin in the apoptotic signaling in colon cancer in vitro and in vivo. We hypothesized that ABJ + Aspirin would produce the most effective anti-proliferative and pro-apoptotic effects in vitro and in vivo. Methods The polyphenolic composition of ABJ was carried out by HPLC-DAD. ABJ (0–30% v/v), Aspirin (0–20 mM), and their mixture were evaluated for their pro-apoptotic effects in human SW480 colorectal cancer cells, followed by human apoptosis proteomic and bioinformatic analysis and in silico docking potential between ABJ components and selected pro-apoptotic targets. For the in vivo assays, colorectal cancer was induced with two injections (separated 1 week each) of azoxymethane (AOM: 15 mg/kg body weight, BW), and treatments were evaluated for its chemopreventive and chemoprotective effects. Hence, 30 male and female Balb/c mice were randomly divided in 5 groups: negative control (basal diet, BD); and four AOM-induced groups: positive control (BD), Aspirin (25 mg/kg BW + BD), ABJ (30% v/v in drinking water ABJ + BD), and ABJ + Aspirin (30% v/v ABJ + 25 mg/kg BW Aspirin + BD). Macroscopic and histopathological parameters were evaluated in vivo. Results The mixture displayed the highest antiproliferative effects (+46%), arrested cell cycle at the G2/M phase, decreased cloning efficiency, but reduced Caspase 3/7 activity, suggesting an alternative apoptotic pathway, compared to untreated SW480 cells. Several pro-apoptotic (cytochrome C, TNFRSF1A, Bax, and Bad) and anti-apoptotic (Hsp70/Hsp32) proteins were decreased. ABJ flavonoids (rutin and kaempferol) exhibited the highest in silico affinity with proteins like TRAILR2 or Catalase. Both chemopreventive and chemoprotective approaches showed similar body/liver weight outcomes, but the mixture displayed the strongest aberrant crypt foci reduction in vivo. The chemopreventive approach was more effective in protecting the colon from AOM. Conclusions Results suggested the potential of ABJ to reduce Aspirin use in the alleviation of colorectal cancer markers in vitro and in vivo, modulating alternate pro-apoptotic signaling. Funding Sources The funding provided by COLCIENCIAS and DGAPA-CTIC-UNAM is appreciated.

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