scholarly journals Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer

2018 ◽  
Vol 115 (26) ◽  
pp. E5990-E5999 ◽  
Author(s):  
Yen-An Tang ◽  
Yu-feng Chen ◽  
Yi Bao ◽  
Sylvia Mahara ◽  
Siti Maryam J. M. Yatim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Treatment Approach ◽  
Hypoxia Inducible Factor ◽  
Intrinsic Resistance ◽  
Molecule Inhibitor ◽  
Potential Biomarker ◽  
Hypoxic Tumor ◽  
Colorectal Cancer Patients ◽  
Resistance To Chemotherapy

Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains not fully understood how CSCs in the hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-inducible factor (HIF-1α) and cancer-associated fibroblasts (CAFs)-secreted TGF-β2 converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting in increased stemness/dedifferentiation and intrinsic resistance to chemotherapy. Genetic or small-molecule inhibitor-based ablation of HIF-1α/TGF-β2−mediated GLI2 signaling effectively reversed the chemoresistance caused by the tumor microenvironment. Importantly, high expression levels of HIF-1α/TGF-β2/GLI2 correlated robustly with the patient relapse following chemotherapy, highlighting a potential biomarker and therapeutic target for chemoresistance in colorectal cancer. Our study thus uncovers a molecular mechanism by which hypoxic colorectal tumor microenvironment promotes cancer cell stemness and resistance to chemotherapy and suggests a potentially targeted treatment approach to mitigating chemoresistance.

scholarly journals The Influence of Tumor Microenvironment on ATG4D Gene Expression in Colorectal Cancer Patients

2018 ◽  
Vol 35 (12) ◽  
Author(s):  
Justyna Gil ◽  
David Ramsey ◽  
Pawel Pawlowski ◽  
Elzbieta Szmida ◽  
Przemyslaw Leszczynski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cancer Patients ◽  
Colorectal Cancer Patients

Circulating cell-free DNA in plasma of colorectal cancer patients - A potential biomarker for tumor burden

2017 ◽  
Vol 26 (4) ◽  
pp. 395-401 ◽  
Author(s):  
Jagdeep Singh Bhangu ◽  
Hossein Taghizadeh ◽  
Tamara Braunschmid ◽  
Thomas Bachleitner-Hofmann ◽  
Christine Mannhalter
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Tumor Burden ◽  
Cell Free Dna ◽  
Free Dna ◽  
Potential Biomarker ◽  
Colorectal Cancer Patients ◽  
Circulating Cell Free Dna

scholarly journals Reduced Plasma Levels of Very-Long-Chain Dicarboxylic Acid 28:4 in Italian and Brazilian Colorectal Cancer Patient Cohorts

Metabolites ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 91 ◽  
Author(s):  
Paul Wood ◽  
Michelle Donohue ◽  
John Cebak ◽  
Taylor Beckmann ◽  
Márcia Messias ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dicarboxylic Acid ◽  
Cancer Patients ◽  
Plasma Levels ◽  
High Resolution Mass Spectrometry ◽  
Sporadic Colorectal Cancer ◽  
Inherited Susceptibility ◽  
Potential Biomarker ◽  
Colorectal Cancer Patients ◽  
Long Chain

Background: There are currently no blood-based biomarkers for early diagnosis of colorectal cancer. Previous research has suggested that very-long-chain dicarboxylic acid (VLCDCA) 28:4 might be such a biomarker. Methods: Using high-resolution mass spectrometry, we analyzed VLCDCA 28:4 in the plasma of colorectal cancer patients in Italian [n = 62] and Brazilian [n = 52] cohorts. Additionally, we investigated individuals diagnosed with familial adenomatous polyposis (FAP; n = 27), one of the most important clinical forms of inherited susceptibility to colorectal cancer. Results: Decrements in plasma levels of VLCDCA 28:4 were monitored in colorectal cancer patients. These decreases were independent of the stage of tumor development and the individual’s age. However, no decrements in VLCDCA 28:4 were monitored in FAP patients. Conclusions: The plasma levels of VLCDCA 28:4 represent a potential biomarker of sporadic colorectal cancer. In addition, it is possible that resupply of this anti-inflammatory lipid may represent a new therapeutic strategy for CRC and inflammatory disorders.

scholarly journals Correlation of tumor microenvironment from biopsy and resection specimens in untreated colorectal cancer patients: a surprising lack of agreement

2020 ◽  
Author(s):  
Phillip M. Kemp Bohan ◽  
Robert C. Chick ◽  
Annelies T. Hickerson ◽  
Lynn M. Messersmith ◽  
Grant M. Williams ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cancer Patients ◽  
Colorectal Cancer Patients

Predictive significance of VEGF and HIF-1α expression in metastatic colorectal cancer patients receiving chemotherapy combined with bevacizumab.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14672-e14672
Author(s):  
Veli Berk ◽  
Kemal Deniz ◽  
Halit Karaca ◽  
Mevlude Inanc ◽  
Oktay Bozkurt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Clinical Benefit ◽  
Hypoxia Inducible Factor ◽  
Therapy Response ◽  
Progression Free Survival ◽  
Vegf Expression ◽  
Primary Tumors ◽  
Colorectal Cancer Patients ◽  
Low Expression

e14672 Background: There is no suggested molecular indicator in identifying which patients will benefit from anti-angiogenic treatment in metastatic colorectal cancer. Over expression of vascular endothelial growth factor (VEGF) and Hypoxia Inducible Factor 1-alpha (HIF-1α) are associated with bad prognosis. In this study, VEGF and HIF-1α expression and their clinical significance are studied in tumor tissues of patients with colorectal cancer receiving treatment with bevacizumab. Methods: VEGF and HIF-1α were observed immunohistochemically in primary tumors of 53 patients. The expressions were separated by evaluating low and high of VEGF and HIF-1α expression. We evaluated whether expression of VEGF and HIF-1α can help to predict treatment response, progression free survival (PFS), and overall survival (OS). Results: Fifty-three patients were enrolled in the study. Median age was 55. VEGF was strongly expressed in 30 patients (57%) whilst low expression was observed in 23 of them (43%). When VEGF expression was evaluated in association with therapy response rates; the clinical benefit rate was 38% in the low expression group whereas it was 62% in high expression group. This difference was statistically significant (p=0.01). In the group with strong VEGF expression PFS was 10 months whereas it was 8 months in the low expression group (p=0.009). When evaluated for OS, 26 months versus 15 months was in favor of highly expressed VEGF group (p=0.03). Highly expressed HIF-1α was found in 29 patients (55%), on the other hand low expressed HIF-1α was detected in 24 (%45) patients. For clinical benefit rates, PFS and OS there was no difference between high and low expressed HIF-1α groups. Conclusions: It has been demonstrated that VEGF and HIF-1α expressions are associated with poor prognosis in several tumors, mainly colorectal carcinomas. With the better understanding of carciogenesis and angiogenesis at molecular level, especially VEGF and HIF-1α became target molecules of the therapy. According to results of our study, VEGF expression is a predictive factor in designating the metastatic colorectal cancer treatment.

scholarly journals Establishment of a Novel Model for Anticancer Drug Resistance in Three-Dimensional Primary Culture of Tumor Microenvironment

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Tatsuya Usui ◽  
Masashi Sakurai ◽  
Shuhei Enjoji ◽  
Hideyoshi Kawasaki ◽  
Koji Umata ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cancer Patients ◽  
Primary Tumor ◽  
Three Dimensional ◽  
Cell Marker ◽  
Organoid Culture ◽  
Colorectal Cancer Patients ◽  
Novel Model ◽  
Tumor Organoids

Tumor microenvironment has been implicated in tumor development and progression. As a three-dimensional tumor microenvironment model, air liquid interface (ALI) organoid culture from oncogene transgenic mouse gastrointestinal tissues was recently produced. However, ALI organoid culture system from tissues of colorectal cancer patients has not been established. Here, we developed an ALI organoid model from normal and tumor colorectal tissues of human patients. Both organoids were successfully generated and showed cystic structures containing an epithelial layer and surrounding mesenchymal stromal cells. Structures of tumor organoids closely resembled primary tumor epithelium. Expression of an epithelial cell marker, E-cadherin, a goblet cell marker, MUC2, and a fibroblast marker, vimentin, but not a myofibroblast marker, α-smooth muscle actin (SMA), was observed in normal organoids. Expression of E-cadherin, MUC2, vimentin, and α-SMA was observed in tumor organoids. Expression of a cancer stem cell marker, LGR5 in tumor organoids, was higher than that in primary tumor tissues. Tumor organoids were more resistant to toxicity of 5-fluorouracil and Irinotecan than colorectal cancer cell lines, SW480, SW620, and HCT116. These findings indicate that ALI organoid culture from colorectal cancer patients may become a novel model that is useful for examining resistance to chemotherapy in tumor microenvironment.

scholarly journals Prevalence and coexistence of KRAS, BRAF, PIK3CA, NRAS, TP53, and APC mutations in Indian colorectal cancer patients: Next-generation sequencing–based cohort study

Tumor Biology ◽  
2017 ◽  
Vol 39 (2) ◽  
pp. 101042831769226 ◽  
Author(s):  
Mayank Jauhri ◽  
Akanksha Bhatnagar ◽  
Satish Gupta ◽  
Manasa BP ◽  
Sachin Minhas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Next Generation Sequencing ◽  
Cancer Patients ◽  
Gene Mutations ◽  
Next Generation ◽  
Kras Mutations ◽  
Pik3ca Mutations ◽  
Potential Biomarker ◽  
Colorectal Cancer Patients ◽  
Generation Sequencing

Colorectal cancer incidences are on a rise in India. In this study, we have analyzed the mutation frequencies of six potential biomarkers, their coexistence, association with clinicopathological characteristics, and tumor location in Indian colorectal cancer patients. Next-generation sequencing was performed to identify mutations in the six potential biomarker genes using formalin-fixed paraffin-embedded tissue blocks of 112 colorectal cancer patients. The mutation frequency observed in KRAS, BRAF, PIK3CA, NRAS, TP53, and APC was 35.7%, 7.1%, 16.1%, 6.3%, 39.3%, and 29.5%, respectively. The significant associations of mutations were KRAS with age less than 60 years (p = 0.041), PIK3CA with males (p = 0.032), tumor stage I–II (p = 0.013), lack of metastasis in lymph nodes (p = 0.040), NRAS with rectum (p = 0.002), and APC with T2 stage of tumor growth (p = 0.013). No single patient harbored mutations in these six genes or any five genes simultaneously. Significance was noted in coexistence of KRAS with APC (p = 0.024) and mutual exclusion of KRAS with BRAF (p = 0.029). PIK3CA exon 9 was observed to be more frequently associated with KRAS mutations than PIK3CA exon 20 (p = 0.072). NRAS mutations were mutually exclusive with BRAF and PIK3CA mutations. As per our knowledge, this is the first next-generation sequencing–based biomarker study in Indian colorectal cancer patients. Frequent coexistence of gene mutations in pairs and triplets suggests that synergistic effect of overlapping mutations might further trigger the disease. In addition, infrequent coexistence of multiple gene mutations hints toward different signaling pathways for colorectal cancer tumorigenesis.

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