Evaluation of the Adenocarcinoma-Associated Gene AGR2 and the Intestinal Stem Cell Marker LGR5 as Biomarkers in Colorectal Cancer

Valladares‐Ayerbes, Manuel; Blanco-Calvo, Moisés; Reboredo, Margarita; Lorenzo-Patiño, María J.; Iglesias-Díaz, Pilar; Haz, Mar; Díaz‐Prado, Silvia; Medina, Vanessa; Santamarina, Isabel; Pértega, Sonia; Figueroa, Angélica; Antón-Aparicio, Luis

doi:10.3390/ijms13044367

Cited by 42 publications

(45 citation statements)

References 44 publications

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“…Our finding confirmed the previous studies indicating higher expression level of Lgr5 in PB of CRC patients compared to control group [57]. We also confirmed that Lgr5 expression was significantly higher in higher stages of CRC.…”

Section: Discussionsupporting

confidence: 95%

“…The correlation between Lgr5 expression level and clinicopathological features as well as clinical outcome of CRC patients has been discussed in depth throughout the literature [37][38][39]. In addition, the diagnostic and prognostic significance of circulating Lgr5 as a potential marker of CRC in PB has been recently reported [57]. Moreover, accumulating evidences have emphasized on the role of DCLK1 as a candidate of CSC markers in CRC patients [44,45].…”

Section: Discussionmentioning

confidence: 98%

“…In addition, analyzing of samples based on the history of neoadjuvant therapy showed a significant increase in DCLK1 expression in patients with preoperative CRT history. Despite of many evidences indicating the relevance of Lgr5 expression pattern to tumor characteristics such as stage, prognosis, and survival [57,58], the specific expression pattern of DCLK1 in neoadjuvant CRT-treated patients is perfectly suited to the concept of CSC. As previously discussed, dividing tumor cells are influenced by CRT and quiescent CSCs are resistant to such kind of therapeutic agents [17][18][19][20].…”

Section: Discussionmentioning

confidence: 98%

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Upregulation of circulating cancer stem cell marker, DCLK1 but not Lgr5, in chemoradiotherapy-treated colorectal cancer patients

et al. 2015

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Cancer stem cell (CSC) markers have attracted considerable attention in tumor diagnostic, prognostic, and therapeutic implications. Detection of cancer stem cells in circulating blood using cancer stem cell markers has received remarkable attention recently. In this study, we aimed to investigate the messenger RNA (mRNA) expression level of Lgr5 and DCLK1 as most proposed colorectal CSC markers in blood circulation also determine the subsequent association to patients' clinical and pathological findings. Peripheral blood mononuclear cells (PBMCs) of 58 patients with colorectal cancer at stage I-IV with 33 out of 58 patients undergoing preoperative chemoradiotherapy (CRT), as well as 58 healthy controls have been isolated and the extracted RNAs were analyzed using real-time PCR. The mRNA expression pattern of CSC markers of patients and controls was compared using ΔΔCt method. The expression level of Lgr5 was significantly higher in colorectal cancer (CRC) patients comparing to healthy group (4.8-fold change, p < 0.001). Also there was a significant increase in expression level of Lgr5 in patients at stages III and IV comparing to stages I and II (p = 0.031) and higher grades (p = 0.039) of CRC. The expression of DCLK1 was also elevated in patients significantly (2.7-fold change, p < 0.001) and the related expression was increased by increasing disease stage (p = 0.025). Combination of DCLK1 and Lgr5 markers was analyzed by logistic regression and proved to be a slightly better marker compared to each marker alone. Interestingly the DCLK1 expression level was significantly higher in patients undergoing preoperative CRT (p = 0.041); however, no association to neoadjuvant CRT was observed for Lgr5. Considering the over-expression of DCLK1 and Lgr5 in circulating blood of CRC patients comparing to controls, our results might emphasize on the presence of CSCs in blood of these patients which might be attributed to their clinical and pathological characteristics and may lead to apply in future clinical implications. Moreover, the higher expression level of DCLK1 in patients undergoing CRT can propose it as a more relevant candidate among CSC markers comparing to Lgr5 for CRC patients.

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Section: Discussionsupporting

confidence: 95%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

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Upregulation of circulating cancer stem cell marker, DCLK1 but not Lgr5, in chemoradiotherapy-treated colorectal cancer patients

et al. 2015

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“…[21][22][23][24][25]31 In this study, the effect of rhES-AuNPs on mCRC tumor growth in vivo was firstly evaluated. The results suggested that rhES-AuNPs experimental group could modulate vascular morphology in mCRC tumor and improve tumor hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Conjugation of gold nanoparticles and recombinant human endostatin modulates vascular normalization via interruption of anterior gradient 2–mediated angiogenesis

Fan

Yang

et al. 2017

Tumour Biol.

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Several studies have revealed the potential of normalizing tumor vessels in anti-angiogenic treatment. Recombinant human endostatin is an anti-angiogenic agent which has been applied in clinical tumor treatment. Our previous research indicated that gold nanoparticles could be a nanoparticle carrier for recombinant human endostatin delivery. The recombinant human endostatin-gold nanoparticle conjugates normalized vessels, which improved chemotherapy. However, the mechanism of recombinant human endostatin-gold nanoparticle-induced vascular normalization has not been explored. Anterior gradient 2 has been reported to be over-expressed in many malignant tumors and involved in tumor angiogenesis. To date, the precise efficacy of recombinant human endostatin-gold nanoparticles on anterior gradient 2-mediated angiogenesis or anterior gradient 2-related signaling cohort remained unknown. In this study, we aimed to explore whether recombinant human endostatin-gold nanoparticles could normalize vessels in metastatic colorectal cancer xenografts, and we further elucidated whether recombinant human endostatin-gold nanoparticles could interrupt anterior gradient 2-induced angiogenesis. In vivo, it was indicated that recombinant human endostatingold nanoparticles increased pericyte expression while inhibit vascular endothelial growth factor receptor 2 and anterior gradient 2 expression in metastatic colorectal cancer xenografts. In vitro, we uncovered that recombinant human endostatin-gold nanoparticles reduced cell migration and tube formation induced by anterior gradient 2 in human umbilical vein endothelial cells. Treatment with recombinant human endostatin-gold nanoparticles attenuated anterior gradient 2-mediated activation of MMP2, cMyc, VE-cadherin, phosphorylation of p38, and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in human umbilical vein endothelial cells. Our findings demonstrated recombinant human endostatin-gold nanoparticles might normalize vessels by interfering anterior gradient 2-mediated angiogenesis in metastatic colorectal cancer.

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“…We believe that it is the stem cells within the circulating tumor cell pool that are responsible for metastatic disease progression: these cells are termed circulating tumor stem cells (CTSC) (33) (Figure 1). This view is bolstered by the presence of stem cell phenotypes CD26+ and CD133+ in CTCs of metastatic CRC patients (44,45) and the finding that increased expression of the exclusive stem cell marker leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) in colorectal tumors indicates a poor prognosis (46,47).…”

Section: The Emerging Circulating Tumor Stem Cell Hypothesismentioning

confidence: 99%

Detection and Clinical Significance of Circulating Tumor Cells in Colorectal Cancer—20 Years of Progress

Hardingham

Grover

Winter

et al. 2015

Mol Med

124

104

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Circulating tumor cells (CTC) may be defined as tumor-or metastasis-derived cells that are present in the bloodstream. The CTC pool in colorectal cancer (CRC) patients may include not only epithelial tumor cells, but also tumor cells undergoing epithelial-mesenchymal transition (EMT) and tumor stem cells. A significant number of patients diagnosed with early stage CRC subsequently relapse with recurrent or metastatic disease despite undergoing "curative" resection of their primary tumor. This suggests that an occult metastatic disease process was already underway, with viable tumor cells being shed from the primary tumor site, at least some of which have proliferative and metastatic potential and the ability to survive in the bloodstream. Such tumor cells are considered to be responsible for disease relapse in these patients. Their detection in peripheral blood at the time of diagnosis or after resection of the primary tumor may identify those early-stage patients who are at risk of developing recurrent or metastatic disease and who would benefit from adjuvant therapy. CTC may also be a useful adjunct to radiological assessment of tumor response to therapy. Over the last 20 years many approaches have been developed for the isolation and characterization of CTC. However, none of these methods can be considered the gold standard for detection of the entire pool of CTC. Recently our group has developed novel unbiased inertial microfluidics to enrich for CTC, followed by identification of CTC by imaging flow cytometry. Here, we provide a review of progress on CTC detection and clinical significance over the last 20 years.

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Evaluation of the Adenocarcinoma-Associated Gene AGR2 and the Intestinal Stem Cell Marker LGR5 as Biomarkers in Colorectal Cancer

Cited by 42 publications

References 44 publications

Upregulation of circulating cancer stem cell marker, DCLK1 but not Lgr5, in chemoradiotherapy-treated colorectal cancer patients

Upregulation of circulating cancer stem cell marker, DCLK1 but not Lgr5, in chemoradiotherapy-treated colorectal cancer patients

Conjugation of gold nanoparticles and recombinant human endostatin modulates vascular normalization via interruption of anterior gradient 2–mediated angiogenesis

Detection and Clinical Significance of Circulating Tumor Cells in Colorectal Cancer—20 Years of Progress

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