Cancers, Vol. 9, Pages 171: Regulation of EMT in Colorectal Cancer: A Culprit in Metastasis

Cancers, Vol. 9, Pages 171: Regulation of EMT in Colorectal Cancer: A Culprit in Metastasis

Cancers doi: 10.3390/cancers9120171

Authors: Trung Vu Pran Datta

Epithelial to mesenchymal transition (EMT) is a process during which cells lose their epithelial characteristics, for instance cell polarity and cell–cell contact, and gain mesenchymal properties, such as increased motility. In colorectal cancer (CRC), EMT is associated with an invasive or metastatic phenotype. In this review, we discuss recent studies exploring novel regulation mechanisms of EMT in CRC, including the identification of new CRC EMT regulators. Upregulation of inducers can promote EMT, leading to increased invasiveness and metastasis in CRC. These inducers can downregulate E-cadherin and upregulate N-cadherin and vimentin (VIM) through modulating EMT-related signaling pathways, for instance WNT/β-catenin and TGF-β, and EMT transcription factors, such as zinc finger E-box binding homeobox 1 (ZEB1) and ZEB2. In addition, several microRNAs (miRNAs), including members of the miR-34 and miR-200 families, are found to target mRNAs of EMT-transcription factors, for example ZEB1, ZEB2, or SNAIL. Downregulation of these miRNAs is associated with distant metastasis and advanced stage tumors. Furthermore, the role of EMT in circulating tumor cells (CTCs) is also discussed. Mesenchymal markers on the surface of EMT CTCs were found to be associated with metastasis and could serve as potential biomarkers for metastasis. Altogether, these studies indicate that EMT is orchestrated by a complicated network, involving regulators of different signaling pathways. Further studies are required to understand the mechanisms underlying EMT in CRC.

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Cancers, Vol. 9, Pages 171: Regulation of EMT in Colorectal Cancer: A Culprit in Metastasis

Cancers, Vol. 9, Pages 171: Regulation of EMT in Colorectal Cancer: A Culprit in Metastasis

Cancers doi: 10.3390/cancers9120171

Authors: Trung Vu Pran Datta

Epithelial to mesenchymal transition (EMT) is a process during which cells lose their epithelial characteristics, for instance cell polarity and cell–cell contact, and gain mesenchymal properties, such as increased motility. In colorectal cancer (CRC), EMT is associated with an invasive or metastatic phenotype. In this review, we discuss recent studies exploring novel regulation mechanisms of EMT in CRC, including the identification of new CRC EMT regulators. Upregulation of inducers can promote EMT, leading to increased invasiveness and metastasis in CRC. These inducers can downregulate E-cadherin and upregulate N-cadherin and vimentin (VIM) through modulating EMT-related signaling pathways, for instance WNT/β-catenin and TGF-β, and EMT transcription factors, such as zinc finger E-box binding homeobox 1 (ZEB1) and ZEB2. In addition, several microRNAs (miRNAs), including members of the miR-34 and miR-200 families, are found to target mRNAs of EMT-transcription factors, for example ZEB1, ZEB2, or SNAIL. Downregulation of these miRNAs is associated with distant metastasis and advanced stage tumors. Furthermore, the role of EMT in circulating tumor cells (CTCs) is also discussed. Mesenchymal markers on the surface of EMT CTCs were found to be associated with metastasis and could serve as potential biomarkers for metastasis. Altogether, these studies indicate that EMT is orchestrated by a complicated network, involving regulators of different signaling pathways. Further studies are required to understand the mechanisms underlying EMT in CRC.

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Human c-SRC kinase (CSK) overexpression makes T cells dummy

Abstract

Adoptive cell therapy with T-cell receptor (TCR)-engineered T cells represents a powerful method to redirect the immune system against tumours. However, although TCR recognition is restricted to a specific peptide–MHC (pMHC) complex, increasing numbers of reports have shown cross-reactivity and off-target effects with severe consequences for the patients. This demands further development of strategies to validate TCR safety prior to clinical use. We reasoned that the desired TCR signalling depends on correct pMHC recognition on the outside and a restricted clustering on the inside of the cell. Since the majority of the adverse events are due to TCR recognition of the wrong target, we tested if blocking the signalling would affect the binding. By over-expressing the c-SRC kinase (CSK), a negative regulator of LCK, in redirected T cells, we showed that peripheral blood T cells inhibited anti-CD3/anti-CD28-induced phosphorylation of ERK, whereas TCR proximal signalling was not affected. Similarly, overexpression of CSK together with a therapeutic TCR prevented pMHC-induced ERK phosphorylation. Downstream effector functions were also almost completely blocked, including pMHC-induced IL-2 release, degranulation and, most importantly, target cell killing. The lack of effector functions contrasted with the unaffected TCR expression, pMHC recognition, and membrane exchange activity (trogocytosis). Therefore, co-expression of CSK with a therapeutic TCR did not compromise target recognition and binding, but rendered T cells incapable of executing their effector functions. Consequently, we named these redirected T cells "dummy T cells" and propose to use them for safety validation of new TCRs prior to therapy.

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Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation

Abstract

Purpose

Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC).

Methods

117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed.

Results

Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5–11.6) vs 5.0 (4.2–5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8–12.9) vs. 5.8 (4.8–6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5–24.1) vs. 7.8 (5.2–10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation.

Conclusions

MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.

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Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation

Abstract

Purpose

Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC).

Methods

117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed.

Results

Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5–11.6) vs 5.0 (4.2–5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8–12.9) vs. 5.8 (4.8–6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5–24.1) vs. 7.8 (5.2–10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation.

Conclusions

MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.

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Comparison of TIVA with different combinations of ketamine–propofol mixtures in pediatric patients

Abstract

Purpose

Adding ketamine to propofol has been suggested to be useful for sedation and general anesthesia. This study aimed to determine the effect of TIVA with different ratios of ketofol on recovery in children.

Methods

Seventy-five children aged 3–12 years and undergoing adenoidectomy and/or tonsillectomy surgery were randomized into three groups. Ratios of 1:5, 1:6.7 and 1:10 ketamine–propofol mixture (ketofol) were prepared in the same syringe for groups I, II and III, respectively. Induction and maintenance of anesthesia were performed with 1:5, 1:6.7 and 1:10 ratios of ketofol in groups I, II and III, respectively. A McFarlan infusion dose regimen was used (15 mg/kg/h for 15 min, 13 mg/kg/h for 15 min, 11 mg/kg/h for 30 min) and infusion rates were decreased for the different ratios. Infusion rates were reduced to 67, 80 and 90% of the McFarlan dose regimen for groups I, II and III, respectively. Extubating time, length of stay in PACU, postoperative PAED and FLACC scores were recorded.

Results

Extubating time was significantly lower [mean 254.3 ± 92.7 s (95% CI 216.6–292.6, p = 0.001)] in group III than in groups I and II [371.3 ± 153 s (308.1–434.48) and 343.2 ± 123.7 s (292.2–394.3), respectively]. Length of stay in the PACU was lower in group III [median 15 min (interquartile range 15–20, p = 0.001)] than in groups I and II: 20 (15–27.5) and 20 min (20–27.5), respectively.

Conclusion

TIVA with a 1:10 ratio of ketofol admixture with a 90% reduction of McFarlan regimen can provide improved recovery conditions.

Trial registration

ClinicalTrials.gov identifier: NCT02848963.

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Human c-SRC kinase (CSK) overexpression makes T cells dummy

Abstract

Adoptive cell therapy with T-cell receptor (TCR)-engineered T cells represents a powerful method to redirect the immune system against tumours. However, although TCR recognition is restricted to a specific peptide–MHC (pMHC) complex, increasing numbers of reports have shown cross-reactivity and off-target effects with severe consequences for the patients. This demands further development of strategies to validate TCR safety prior to clinical use. We reasoned that the desired TCR signalling depends on correct pMHC recognition on the outside and a restricted clustering on the inside of the cell. Since the majority of the adverse events are due to TCR recognition of the wrong target, we tested if blocking the signalling would affect the binding. By over-expressing the c-SRC kinase (CSK), a negative regulator of LCK, in redirected T cells, we showed that peripheral blood T cells inhibited anti-CD3/anti-CD28-induced phosphorylation of ERK, whereas TCR proximal signalling was not affected. Similarly, overexpression of CSK together with a therapeutic TCR prevented pMHC-induced ERK phosphorylation. Downstream effector functions were also almost completely blocked, including pMHC-induced IL-2 release, degranulation and, most importantly, target cell killing. The lack of effector functions contrasted with the unaffected TCR expression, pMHC recognition, and membrane exchange activity (trogocytosis). Therefore, co-expression of CSK with a therapeutic TCR did not compromise target recognition and binding, but rendered T cells incapable of executing their effector functions. Consequently, we named these redirected T cells "dummy T cells" and propose to use them for safety validation of new TCRs prior to therapy.

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