Expression of HER2 in Colorectal Cancer Does Not Correlate with Prognosis

Estimation of HER2 membranous expression is routinely used in breast and gastric cancers, as both a prognostic and a predictive factor. To date there is no evidence for similar application of HER2 expression in colorectal cancer (CRC) cells. In CRC, HER2 is sometimes overexpressed in the cell membrane and very often in the cytoplasm. This study was conducted to determine possible correlations between both membranous and cytoplasmatic expression of HER2 in CRC cells and the outcome of the disease. The prognostic significance of combined staining intensity in the cell membrane and cytoplasm in the entire CRC cell was also investigated. HER2 expression in resectable colorectal adenocarcinoma cells was evaluated by immunohistochemistry in specimens taken from 202 patients. The percentage of cancer cells with membranous or cytoplasmatic reactions and the staining intensity of the reaction in the whole cell were recorded. A membranous reaction was present in 27% of cases, and cytoplasmatic reaction in 66% of cases. The total staining intensity in the entire cell was evaluated as moderate (2+) in 32% of cases and strong (3+) staining in 15%. There was no correlation found between either membranous or cytoplasmatic HER2 expression and survival. Furthermore combined staining intensity did not provide any prognostic information. We conclude that HER2 expression in CRC does not correlate with prognosis.

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Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer

Molecules ◽

10.3390/molecules26237375 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7375

Author(s):

Paulina Lewandowska ◽

Izabela Szczuka ◽

Iwona Bednarz-Misa ◽

Berenika M. Szczęśniak-Sięga ◽

Katarzyna Neubauer ◽

...

Keyword(s):

Colorectal Cancer ◽

Colorectal Adenocarcinoma ◽

Normal Mucosa ◽

Colorectal Tumors ◽

Adjacent Tissue ◽

Inflammatory Drug ◽

Chemokine Expression ◽

Adenocarcinoma Cells ◽

Thiazine Ring ◽

N Stage

The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the expression/secretion of macrophage-associated chemokines (RTqPCR/Luminex xMAP) in colorectal adenocarcinoma cells, and on the expression of upstream the non-steroidal anti-inflammatory drug (NSAID)-activated genes NAG1, NFKBIA, MYD88, and RELA, as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated CCL4 9.9-fold, but otherwise the classic oxicams had a negligible/non-significant effect. Novel analogues with a thiazine ring substituted with arylpiperazine and benzoyl moieties significantly modulated chemokine expression to varying degree, upregulated NAG1 and NFKBIA, and downregulated MYD88. They inhibited CCL3 and CCL4, and their effect on CCL2 and CXCL2 depended on the dose and exposure. The propylene linker between thiazine and piperazine nitrogens and one arylpiperazine fluorine substituent characterized the most effective analogue. Only CCL19 and CXCL2 were not upregulated in tumors, nor was CXCL2 in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, CCL4 and CXCL2 were upregulated, while CCL2, CCL8, and CCL19 were downregulated in tumors. Tumor CCL2 and CCL7 increased along with advancing T and CCL3, and CCL4 along with the N stage. The introduction of arylpiperazine and benzoyl moieties into the oxicam scaffold yields effective modulators of chemokine expression, which act by upregulating NAG1 and interfering with NF-κB signaling.

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A serine protease extracted from Trichosanthes kirilowii induces apoptosis via the PI3K/AKT-mediated mitochondrial pathway in human colorectal adenocarcinoma cells

Food & Function ◽

10.1039/c5fo00760g ◽

2016 ◽

Vol 7 (2) ◽

pp. 843-854 ◽

Cited By ~ 14

Author(s):

Li Song ◽

Jiao Chang ◽

Zhuoyu Li

Keyword(s):

Colorectal Cancer ◽

Serine Protease ◽

Colorectal Adenocarcinoma ◽

Mitochondrial Pathway ◽

Adenocarcinoma Cells ◽

Trichosanthes Kirilowii ◽

Dependent Pathway ◽

Cancer Activity ◽

Novel Protein

A novel protein TKP extracted from T. kirilowii fruit exerted potential anti-colorectal cancer activity by inducing apoptosis, which was regulated by the PI3K/AKT-mediated mitochondria-dependent pathway.

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Immunohistochemical test for MLH1 and MSH2 is an independent prognostic factor in sporadic colorectal cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.4126 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 4126-4126 ◽

Cited By ~ 1

Author(s):

K. Öhrling ◽

D. Edler ◽

M. Hallström ◽

M. Karlberg ◽

P. Ragnhammar

Keyword(s):

Colorectal Cancer ◽

Prognostic Factor ◽

Protein Expression ◽

Mismatch Repair ◽

Predictive Factor ◽

Immunohistochemical Analysis ◽

Sporadic Colorectal Cancer ◽

Prognostic Information ◽

Entire Study ◽

Dna Mismatch

4126 Background: Microsatellite instability (MSI) is the hallmark of a defective DNA mismatch repair (MMR) and occurs in 10- 20 % of sporadic colorectal cancer (CRC). The loss of the MLH1 protein is the cause of MSI in almost all sporadic colorectal MSI tumours. The second most common protein to be lost is MSH2. There is evidence that MSI is a prognostic factor in CRC. The role of MSI status as a predictive factor of benefit from adjuvant 5-fluorouracil (5-FU) based chemotherapy is controversial. Methods: Monoclonal antibodies that recognize the mismatch repair protein by immunohistochemistry (IHC) have been commercially available for several years. Previous reports have found a strong correlation between MMR results obtained by immunohistochemical and genetic analysis. This study included 1006 CRC patients (488 Stage II and 518 Stage III) with a median follow-up of 5 years. The patients were included in Nordic trials randomised between surgery alone and surgery plus adjuvant 5-FU. The MMR status was retrospectively assessed on paraffin-embedded formalin-fixed samples using IHC. Results: One hundred fifty seven patients (15.6 %) showed a loss of MMR protein expression (139 MLH1 negative, 15 MSH2 negative and 3 MLH1+MSH2 negative) and were classified as MMR protein negative. A normal MMR protein expression was found in 851 patients who were defined as MMR protein positive. The median overall survival (OS) was 84 months (range 2–181 months). MMR protein expression was a significant prognostic marker in the entire study group where a better OS was seen among patients with MMR protein negative carcinomas compared to patients with MMR protein positive tumours (p=0.005). In multivariate analysis the MMR protein expression was significantly associated with OS, (hazard ratio for death, 0.67 [95 per cent confidence interval, 0.38 to 0.96]; p=0.008). However, in this study the MMR status did not predict response to 5-FU adjuvant chemotherapy. Conclusions: This study reveals that immunohistochemical analysis of MLH1 and MSH2 expression can yield important prognostic information but is not a predictive factor in sporadic CRC. No significant financial relationships to disclose.

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Clinical significance of serum angiopoietin-like protein 2 in colorectal cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.417 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 417-417

Author(s):

Takahito Kitajima ◽

Yuji Toiyama ◽

Tadanobu Shimura ◽

Shozo Ide ◽

Hiroki Imaoka ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Cell ◽

Cancer Patients ◽

Clinical Significance ◽

Prognostic Significance ◽

Disease Free Survival ◽

Staining Intensity ◽

High Serum ◽

Highly Correlated ◽

Colorectal Cancer Patients

417 Background: Angiopoietin-like protein 2 (ANGPTL2) is a secreted protein belonging to the angiopoietin family. It has been reported to act as a causative mediator of chronic inflammation and metabolic abnormalities. ANGPTL2 increases inflammatory carcinogenesis in several cancers, and its expression in tumor cells is highly correlated with the frequency of tumor cell metastasis through increased tumor angiogenesis and tumor cell epithelial-to-mesenchymal transitions. However, to our own knowledge, clinical significance of serum ANGPTL2 in cancer patients remains unknown. The aim of this study was to quantify serum ANGPTL2 level using ELISA, and to evaluate its clinical and prognostic significance in patients with colorectal cancer (CRC). Methods: We quantified serum ANGPTL2 levels from 194 CRC patients and normal 48 controls (NC) by ELISA. Next, we investigated ANGPTL2 expression in matched CRC tissues (n=194) by immunohistochemistry (IHC) to identify the source of circulating ANGPTL2. The IHC score of ANGPTL2 was determined on the basis of both staining intensity and the percentage of positive cells. Results: Serum ANGPTL2 levels were significantly higher in CRC than in NC (p<0.01) and gradually increased according to TNM stage progression. Serum ANGPTL2 levels discriminated CRC from NC with high accuracy (AUC=0.837). High serum ANGPTL2 was significantly associated with larger tumor size (p=0.03), undifferentiated adenocarcinoma (p=0.03), advanced T stage (p<0.01), peritoneal metastasis (p<0.01). In addition, Kaplan–Meier curves revealed that high serum ANGPTL2 were significantly associated with poor disease free survival (p=0.01) and overall survival (p=0.03). Interestingly, ANGPTL2 levels in serum from CRC patients closely correlated with IHC scores of cytoplasmic ANGPTL2 expression in matched CRC tissues (r=0.14, p=0.03). Conclusions: Serum ANGPTL2, which might be derived from primary CRC tumor, has strong potential to serve as a noninvasive biomarker for CRC diagnosis and prognosis.

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Immunohistochemical Test for MLH1 and MSH2 Expression Predicts Clinical Outcome in Stage II and III Colorectal Cancer Patients

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.2433 ◽

2006 ◽

Vol 24 (15) ◽

pp. 2359-2367 ◽

Cited By ~ 143

Author(s):

Giovanni Lanza ◽

Roberta Gafà ◽

Alessandra Santini ◽

Iva Maestri ◽

Laura Guerzoni ◽

...

Keyword(s):

Colorectal Cancer ◽

Adjuvant Chemotherapy ◽

Clinical Outcome ◽

Cancer Patients ◽

Prognostic Significance ◽

Stage Ii ◽

Stage Iii ◽

Prognostic Information ◽

Colorectal Cancer Patients ◽

Risk Of Cancer

Purpose To evaluate the prognostic significance of DNA mismatch repair (MMR) status in a large series of stage II and III colorectal cancer patients. The relationship among MMR status, adjuvant chemotherapy, and clinical outcome was also investigated. Patients and Methods The study included 718 patients with colorectal adenocarcinoma (393 stage II and 325 stage III) who underwent curative surgical resection. MMR status was determined by immunohistochemical analysis of MLH1 and MSH2 expression. Microsatellite instability (MSI) was assessed in 363 patients using mononucleotide and dinucleotide markers. Results One hundred fourteen (15.9%) carcinomas showed abnormal MMR protein (MMRP) expression (96 MLH1 negative and 18 MSH2 negative) and were classified as MMRP negative, whereas 604 tumors demonstrated normal MLH1/MSH2 immunoreactivity (MMRP positive). MLH1/MSH2 expression was closely related to MSI status (P < .001) and several clinicopathologic features. Patients with MMRP-negative carcinomas demonstrated a marked reduction in the risk of cancer-related death with respect to patients with MMRP-positive tumors (hazard ratio, 0.2579; 95% CI, 0.1289 to 0.5159). A better clinical outcome for patients with MMRP-negative tumors was observed in both stage II (P = .0006) and stage III (P = .0052) disease. In stage III disease, the survival advantage conferred by MMRP-negative tumors was more evident among patients treated with surgery alone than among patients who received adjuvant chemotherapy. A nonsignificant trend for survival benefit from adjuvant chemotherapy was observed among patients with MMRP-positive carcinomas but not among those with MMRP-negative carcinomas. Conclusion Immunohistochemical testing for MLH1/MSH2 expression provides useful prognostic information for the management of stage II and III colorectal cancer patients.

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Expression of the Deleted in Colorectal Cancer Gene Is Related to Prognosis in DNA Diploid and Low Proliferative Colorectal Adenocarcinoma

Journal of Clinical Oncology ◽

10.1200/jco.1999.17.6.1745 ◽

1999 ◽

Vol 17 (6) ◽

pp. 1745-1745 ◽

Cited By ~ 41

Author(s):

Xiao-Feng Sun ◽

Sabine Rütten ◽

Hong Zhang ◽

Bo Nordenskjöld

Keyword(s):

Colorectal Cancer ◽

Colorectal Adenocarcinoma ◽

Prognostic Significance ◽

S Phase ◽

Phase Fraction ◽

Primary Tumors ◽

Deleted In Colorectal Cancer ◽

Node Metastases ◽

Dcc Gene ◽

Colorectal Adenocarcinomas

PURPOSE: Whether or not the deleted in colorectal cancer (DCC) gene is implicated in metastases or in predicting prognosis in patients with colorectal cancer has not previously been substantiated. Our aims were to investigate DCC expression in primary colorectal cancers and in metastases to identify any prognostic significance. PATIENTS AND METHODS: DCC expression was examined immunohistochemically in 195 primary colorectal adenocarcinomas and in 23 paired primary tumors and lymph node metastases. DNA content and S-phase fraction were measured by flow cytometry. RESULTS: The absence of DCC expression was observed in 55 primary tumors (28%). DCC negativity was significantly related to poor prognosis in patients with DNA diploid tumors (P = .03) and those with a low S-phase fraction (< 5%, P = .02) but not in patients with nondiploid tumors or those with a higher S-phase fraction. Furthermore, DCC expression retained its prognostic significance in the diploid subgroup after adjusting for sex, age, site, stage, growth pattern, and differentiation (P = .01). DCC expression was similar in primary tumors and their metastases. CONCLUSION: The absence of DCC predicted a poor outcome in the patients with diploid tumors and those tumors with a low S-phase fraction. Immunohistochemistry may be considered as a practical test to assess prognosis in this subgroup of patients.

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Serum DJ-1 Is a Biomarker of Colorectal Cancer and DJ-1 Activates Mitophagy to Promote Colorectal Cancer Progression

Cancers ◽

10.3390/cancers13164151 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4151

Author(s):

William Tzu-Liang Chen ◽

Han-Bin Yang ◽

Tao-Wei Ke ◽

Wen-Ling Liao ◽

Shih-Ya Hung

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Cancer Cell ◽

Cancer Progression ◽

Colorectal Adenocarcinoma ◽

Reactive Oxygen Species Generation ◽

Cancer Drug ◽

Adenocarcinoma Cells ◽

Colorectal Cancer Progression ◽

Colorectal Cancer Patients

Colorectal cancer is the second most common cancer and the third cancer-associated death in Taiwan. Currently used serum markers for detecting colorectal cancer lack excellent diagnostic accuracy, which results in colorectal cancer being often recognized too late for successful therapy. Mitophagy is the selective autophagic degradation of damaged or excessive mitochondria. DJ-1 is an antioxidant protein that attenuates oxidative stress and maintains mitochondrial quality through activating mitophagy. Mitophagy activation contributes to anti-cancer drug resistance. However, the role of DJ-1-induced mitophagy in colorectal cancer progression remains unclear. In the present study, we collected matched tumor and adjacent normal tissues and serum from patients and cancer cells to demonstrate the clinical value and physiological function of DJ-1 in colorectal cancer. We found that DJ-1 increased in tumor tissues and serum; it was positively correlated with TNM (tumor-node-metastasis) stages of colorectal cancer patients. Through stable knockdown DJ-1 expression in metastatic colorectal adenocarcinoma cells SW620, DJ-1 knockdown inhibited cancer cell survival, migration, and colony formation. In SW620 cells, DJ-1 knockdown induced an incomplete autophagic response that did not affect ATP production; DJ-1 knockdown enhanced intracellular reactive oxygen species generation and damaged mitochondrial accumulation and mitophagy inhibition. It suggests that DJ-1 knockdown inhibits mitophagy that causes metastatic colorectal adenocarcinoma cells to be unable to remove damaged mitochondria and further enhance cancer cell apoptosis. Our data indicate that DJ-1 might be clinically valuable as serum and tissue biomarkers for predicting the TNM stage in colorectal cancer patients. Since DJ-1-induced mitophagy promotes tumor progression, DJ-1 inhibition is a potential therapeutic strategy for colorectal cancer treatment.

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The fatty acid derivative palmitoylcarnitine abrogates colorectal cancer cell survival by depleting glutathione

AJP Cell Physiology ◽

10.1152/ajpcell.00319.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. C1278-C1288 ◽

Cited By ~ 2

Author(s):

Patrick C. Turnbull ◽

Meghan C. Hughes ◽

Christopher G. R. Perry

Keyword(s):

Colorectal Cancer ◽

Cell Survival ◽

Cancer Cell ◽

Colorectal Adenocarcinoma ◽

Breast Adenocarcinoma ◽

Mcf7 Cells ◽

Ht29 Cells ◽

Adenocarcinoma Cells ◽

Hct 116 ◽

The Relationship

Previous evidence suggests that palmitoylcarnitine incubations trigger mitochondrial-mediated apoptosis in HT29 colorectal adenocarcinoma cells, yet nontransformed cells appear insensitive. The mechanism by which palmitoylcarnitine induces cancer cell death is unclear. The purpose of this investigation was to examine the relationship between mitochondrial kinetics and glutathione buffering in determining the effect of palmitoylcarnitine on cell survival. HT29 and HCT 116 colorectal adenocarcinoma cells, CCD 841 nontransformed colon cells, and MCF7 breast adenocarcinoma cells were exposed to 0 μM, 50 μM, and 100 μM palmitoylcarnitine for 24–48 h. HCT 116 and HT29 cells showed decreased cell survival following palmitoylcarnitine compared with CCD 841 cells. Palmitoylcarnitine stimulated H2O2 emission in HT29 and CCD 841 cells but increased it to a greater level in HT29 cells due largely to a higher basal H2O2 emission. This greater H2O2 emission was associated with lower glutathione buffering capacity and caspase-3 activation in HT29 cells. The glutathione-depleting agent buthionine sulfoximine sensitized CCD 841 cells and further sensitized HT29 cells to palmitoylcarnitine-induced decreases in cell survival. MCF7 cells did not produce H2O2 when exposed to palmitoylcarnitine and were able to maintain glutathione levels. Furthermore, HT29 cells demonstrated the lowest mitochondrial oxidative kinetics vs. CCD 841 and MCF7 cells. The results demonstrate that colorectal cancer is sensitive to palmitoylcarnitine due in part to an inability to prevent oxidative stress through glutathione-redox coupling, thereby rendering the cells sensitive to elevations in H2O2. These findings suggest that the relationship between inherent metabolic capacities and redox regulation is altered early in response to palmitoylcarnitine.

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Absence of Autophagy-Related Proteins Expression Is Associated with Poor Prognosis in Patients with Colorectal Adenocarcinoma

Gastroenterology Research and Practice ◽

10.1155/2014/179586 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 23

Author(s):

Ji Hye Choi ◽

Young-Seok Cho ◽

Yoon Ho Ko ◽

Soon Uk Hong ◽

Jin Hee Park ◽

...

Keyword(s):

Colorectal Cancer ◽

Poor Prognosis ◽

Colorectal Adenocarcinoma ◽

Prognostic Markers ◽

Prognostic Significance ◽

Degradation Process ◽

Clinicopathological Parameters ◽

Poor Clinical Outcome ◽

Expression Levels ◽

Related Proteins

Background/Aim.Autophagy, a cellular degradation process, has paradoxical roles in tumorigenesis and the progression of human cancers. The aim of this study was to investigate the expression levels of autophagy-related proteins in colorectal cancer (CRC) and to evaluate their prognostic significance.Methods.This study is a retrospective review of immunohistochemical and clinicopathological data. All specimens evaluated were obtained from 263 patients with colorectal cancer who had undergone surgery between November 1996 and August 2007. The primary outcomes measured were the expression levels of three autophagy-related proteins (ATG5, BECN1/Beclin 1, and Microtubule-associated protein 1 light chain 3B (LC3B)) by immunohistochemistry and its association in clinicopathological parameters and patient survival.Results.The autophagy-related protein expression frequencies were 65.1% (151/232) for ATG5, 71.3% (174/244) for BECN1, and 74.7% (186/249) for LC3B for the 263 patients. Correlation between the expression of autophagy-related proteins was significant for all protein pairs. Multivariate analysis showed that negative LC3B expression and absence of autophagy-related proteins expression were independently associated with poor prognosis.Conclusion.Absence of autophagy-related proteins expression is associated with poor clinical outcome in CRC, suggesting that these proteins have potential uses as novel prognostic markers.

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Ideal 1:1 stoichiometry curcumin inclusion complex induced potential apoptosisin colorectal adenocarcinoma cells: The clear image of necrosis and functionalized dying effect

Current Signal Transduction Therapy ◽

10.2174/1574362414666190625125838 ◽

2019 ◽

Vol 14 ◽

Author(s):

Kavitha K ◽

Muthu Mohamed J ◽

Chitra Karthikeyini S

Keyword(s):

Colorectal Cancer ◽

Cell Death ◽

Cell Growth ◽

Inclusion Complex ◽

Colorectal Adenocarcinoma ◽

Phase Solubility ◽

Adenocarcinoma Cell ◽

Adenocarcinoma Cells ◽

Ic50 Value ◽

Hot Melt

Background: This study investigates the inclusion complex of curcumin (CMN) enhance the solubility, which can be utilized for the treatment of colorectal cancer (CRC) greater to free CMN. Methods: CMN solid dispersion (SD) prepared by a hot melt method using CMN with several carriers of poloxamers (P-407 and P-188), gelucire 50/13 (GLR) and mannitol (MNT). Prior, molecular modelling and phase solubility studieswere performed with drug and carriers. The SD characterized by in vitrodrug release, SEM and functionalize dyeing test. Additionally, the cytotoxicity and image of apoptosisresolved to utilize the colorectal adenocarcinoma cell lines. Results: The result showed that CMN-P-407 inclusion complex produced significant properties towards solubility (318 ± 14.46 fold) and dissolution (91 ± 0.431% at 30 min). Similarly, these data fit with insilico model. The IC50 value for inclusion complex found to be 74 and 52 µM/mL, while that for free CMN ranged from 146 and 116 µM/mL on the SW480 and Caco-2 cells respectively. Apoptosis study described that the cells are undergoing cell death by apoptosis and the small number of necrosis. Conclusion: The profound efﬁciency of CMN-P-407 SD indicated its potential application for CRC treatment by showing a higher capability of inhibiting cell growth compared to that of free CMN.

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