Colorectal cancer (CRC) is a highly heterogeneous disease both from a molecular and clinical perspective. Several distinct molecular entities, such as microsatellite instability (MSI), have been ...defined that make up biologically distinct subgroups with their own clinical course. Recent data indicated that CRC can be best segregated into four groups called consensus molecular subtypes (CMS1-4), each of which has a unique biology and gene expression pattern. In order to develop improved, subtype-specific therapies and to gain insight into the molecular wiring and origin of these subtypes, reliable models are needed. This study was designed to determine the heterogeneity and identify the presence of CMSs in a large panel of CRC cell lines, primary cultures and patient-derived xenografts (PDX). We provide a repository encompassing this heterogeneity and moreover describe that a large part of the models can be robustly assigned to one of the four CMSs, independent of the stromal contribution. We subsequently validate our CMS stratification by functional analysis which for instance shows mesenchymal enrichment in CMS4 and metabolic dysregulation in CMS3. Finally, we observe a clear difference in sensitivity to chemotherapy-induced apoptosis, specifically between CMS2 and CMS4. This relates to the in vivo efficacy of chemotherapy, which delays outgrowth of CMS2, but not CMS4 xenografts. Combined our data indicate that molecular subtypes are faithfully modelled in CRC cell cultures and PDXs, representing tumour cell intrinsic and stable features. This repository provides researchers with a platform to study CRC using the existing heterogeneity.
Patient‐derived xenograft (PDX) models have become an important asset in translational cancer research. However, to provide a robust preclinical platform, PDXs need to accommodate the tumor ...heterogeneity that is observed in patients. Colorectal cancer (CRC) can be stratified into four consensus molecular subtypes (CMS) with distinct biological and clinical features. Surprisingly, using a set of CRC patients, we revealed the partial representation of tumor heterogeneity in PDX models. The epithelial subtypes, the largest subgroups of CRC subtype, were very ineffective in establishing PDXs, indicating the need for further optimization to develop an effective personalized therapeutic approach to CRC. Moreover, we showed that tumor cell proliferation was associated with successful PDX establishment and able to distinguish patient with poor clinical outcomes within CMS2 group.
What's new?
Patient‐derived xenograft (PDX) models have become an important asset in translational cancer research. However, colorectal cancer (CRC) can be stratified into four consensus molecular subtypes (CMS) with distinct biological and clinical features, and to what extent the existing CRC PDX collection represents the inter‐patient heterogeneity remains an open question. This study identifies a subtype‐specific bias in the establishment of PDXs from CRC patients, leaving the major subtype CMS2 strongly underrepresented. Additionally, the findings suggest that further classification within CMS can be achieved. For CMS2, the proliferation‐related marker Ki67 may thus help refine patient classification, estimate prognosis, and guide treatment decisions.
Colon cancer is a clinically diverse disease. This heterogeneity makes it difficult to determine which patients will benefit most from adjuvant therapy and impedes the development of new targeted ...agents. More insight into the biological diversity of colon cancers, especially in relation to clinical features, is therefore needed. We demonstrate, using an unsupervised classification strategy involving over 1,100 individuals with colon cancer, that three main molecularly distinct subtypes can be recognized. Two subtypes have been previously identified and are well characterized (chromosomal-instable and microsatellite-instable cancers). The third subtype is largely microsatellite stable and contains relatively more CpG island methylator phenotype-positive carcinomas but cannot be identified on the basis of characteristic mutations. We provide evidence that this subtype relates to sessile-serrated adenomas, which show highly similar gene expression profiles, including upregulation of genes involved in matrix remodeling and epithelial-mesenchymal transition. The identification of this subtype is crucial, as it has a very unfavorable prognosis and, moreover, is refractory to epidermal growth factor receptor-targeted therapy.
To investigate the safety of laparoscopic colorectal cancer resections in a nationwide population-based study.
Although laparoscopic techniques are increasingly used in colorectal cancer surgery, ...little is known on results outside trials. With the fast introduction of laparoscopic resection (LR), questions were raised about safety.
Of all patients who underwent an elective colorectal cancer resection in 2010 in the Netherlands, 93% were included in the Dutch Surgical Colorectal Audit. Short-term outcome after LR, open resection (OR), and converted LR were compared in a generalized linear mixed model. We further explored hospital differences in LR and conversion rates.
A total of 7350 patients, treated in 90 hospitals, were included. LR rate was 41% with a conversion rate of 15%. After adjustment for differences in case-mix, LR was associated with a lower risk of mortality (odds ratio 0.63, P < 0.01), major morbidity (odds ratio 0.72, P < 0.01), any complications (odds ratio 0.74, P < 0.01), hospital stay more than 14 days (odds ratio 0.71, P < 0.01), and irradical resections (odds ratio 0.68, P < 0.01), compared to OR. Outcome after conversion was similar to OR (P > 0.05). A large variation in LR and conversion rates among hospitals was found; however, the difference in outcome associated with operative techniques was not influenced by hospital of treatment.
Use of laparoscopic techniques in colorectal cancer surgery in the Netherlands is safe and results are better in short-term outcome than open surgery, irrespective of the hospital of treatment. Outcome after conversion was similar to OR.
Purpose
Is it possible to eliminate metastasised chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) cells from ovarian cortex fragments by inhibition of Aurora B/C kinases (AURKB/C) ...without compromising ovarian tissue or follicles?
Methods
Human ovarian cortex tissue with experimentally induced tumour foci of CML, AML and primary cells of AML patients were exposed to a 24h treatment with 1 μM GSK1070916, an AURKB/C inhibitor, to eliminate malignant cells by invoking mitotic catastrophe. After treatment, the inhibitor was removed, followed by an additional culture period of 6 days to allow any remaining tumour cells to form new foci. Ovarian tissue integrity after treatment was analysed by four different assays. Appropriate controls were included in all experiments.
Results
Foci of metastasised CML and AML cells in ovarian cortex tissue were severely affected by a 24h ex vivo treatment with an AURKB/C inhibitor, leading to the formation of multi-nuclear syncytia and large-scale apoptosis. Ovarian tissue morphology and viability was not compromised by the treatment, as no significant difference was observed regarding the percentage of morphologically normal follicles, follicular viability, glucose uptake or in vitro growth of small follicles between ovarian cortex treated with 1 μM GSK1070916 and the control.
Conclusion
Purging of CML/AML metastases in ovarian cortex is possible by targeting the Mitotic Catastrophe Signalling Pathway using GSK1070916 without affecting the ovarian tissue. This provides a therapeutic strategy to prevent reintroduction of leukaemia and enhances safety of autotransplantation in leukaemia patients currently considered at high risk for ovarian involvement.
Plasma oxalate was measured with use of the enzyme oxalate oxidase (EC 1.2.3.4; normal values 3.3 +/- 1.5 mumol/L, n = 24) in 50 patients with different degrees of renal failure. The following mean ...concentrations +/- SD (in mumol/L) were found: for glomerular diseases, 12.7 +/- 7.8 (n = 21); tubular diseases, 20.4 +/- 14.0 (n = 16); chronic renal failure before dialysis, 32.5 +/- 13.5, and after dialysis, 17.8 +/- 3.8 (n = 10); and primary hyperoxalemia, 72.2 +/- 14.5 14.5 (n = 2). The course of plasma oxalate was followed in one of these two patients after renal transplantation and in a patient recovering from acute tubular necrosis. No significant differences were found between patients with glomerular and tubular disorders. Overall, plasma oxalate was correlated with plasma creatinine in patients with glomerular and tubular diseases and dialysis patients (r = .84, P less than .001). Patients with primary hyperoxalemia had values outside the 95% confidence area of the regression line. It is concluded that the values obtained with this method, although probably still tending to overestimate the true oxalate concentration to some extent, provide reliable information about relative differences in plasma oxalate levels. In patients with terminal renal failure, plasma oxalate sometimes rises to levels at which deposition of calcium oxalate in tissues can occur.
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