CD44: More than a mere stem cell marker Morath, I.; Hartmann, T.N.; Orian-Rousseau, V.
The international journal of biochemistry & cell biology,
December 2016, 2016-12-00, 20161201, Letnik:
81, Številka:
Pt A
Journal Article
Recenzirano
CD44 is a cell adhesion molecule that plays an important role in tumor progression and metastasis. The role of CD44 in tumorigenesis is due to its binding to extracellular matrix components, ...including hyaluronan (HA) and osteopontin (OPN), and to messenger molecules, such as growth factors present in the tumor microenvironment. HA and OPN are highly abundant in the leukemic stem cell niche and in solid tumors of various cancer types, where they contribute to the maintenance of the stemness of malignant cells. CD44 has consequently been recognized as a cancer stem cell marker in several types of cancers, which has been a topic of much recent research. In this review we have addressed the question of how CD44 might promote cancer cell stemness by interacting with extracellular matrix components, growth factors and cytokines.
Summary Background Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide—which have been used to treat soft-tissue sarcoma for more than 30 years—still have an ...important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. We assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone. Methods We did this phase 3 randomised controlled trial (EORTC 62012) at 38 hospitals in ten countries. We included patients with locally advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, age 18–60 years with a WHO performance status of 0 or 1. They were randomly assigned (1:1) by the minimisation method to either doxorubicin (75 mg/m2 by intravenous bolus on day 1 or 72 h continuous intravenous infusion) or intensified doxorubicin (75 mg/m2 ; 25 mg/m2 per day, days 1–3) plus ifosfamide (10 g/m2 over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomisation was stratified by centre, performance status (0 vs 1), age (<50 vs ≥50 years), presence of liver metastases, and histopathological grade (2 vs 3). Patients were treated every 3 weeks till progression or unacceptable toxic effects for up to six cycles. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov , number NCT00061984. Findings Between April 30, 2003, and May 25, 2010, 228 patients were randomly assigned to receive doxorubicin and 227 to receive doxorubicin and ifosfamide. Median follow-up was 56 months (IQR 31–77) in the doxorubicin only group and 59 months (36–72) in the combination group. There was no significant difference in overall survival between groups (median overall survival 12·8 months 95·5% CI 10·5–14·3 in the doxorubicin group vs 14·3 months 12·5–16·5 in the doxorubicin and ifosfamide group; hazard ratio HR 0·83 95·5% CI 0·67–1·03; stratified log-rank test p=0·076). Median progression-free survival was significantly higher for the doxorubicin and ifosfamide group (7·4 months 95% CI 6·6–8·3) than for the doxorubicin group (4·6 months 2·9–5·6; HR 0·74 95% CI 0·60–0·90, stratified log-rank test p=0·003). More patients in the doxorubicin and ifosfamide group than in the doxorubicin group had an overall response (60 26% of 227 patients vs 31 14% of 228; p<0·0006). The most common grade 3 and 4 toxic effects—which were all more common with doxorubicin and ifosfamide than with doxorubicin alone—were leucopenia (97 43% of 224 patients vs 40 18% of 223 patients), neutropenia (93 42% vs 83 37%), febrile neutropenia (103 (46%) vs 30 13%), anaemia (78 35% vs 10 5%), and thrombocytopenia (75 33%) vs one <1%). Interpretation Our results do not support the use of intensified doxorubicin and ifosfamide for palliation of advanced soft-tissue sarcoma unless the specific goal is tumour shrinkage. These findings should help individualise the care of patients with this disease. Funding Cancer Research UK, EORTC Charitable Trust, UK NHS, Canadian Cancer Society Research Institute, Amgen.
Summary Background Fluorouracil-based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. We investigated the efficacy and safety of substituting ...fluorouracil with the oral prodrug capecitabine. Methods This randomised, open-label, multicentre, non-inferiority, phase 3 trial began in March, 2002, as an adjuvant trial comparing capecitabine-based chemoradiotherapy with fluorouracil-based chemoradiotherapy, in patients aged 18 years or older with pathological stage II–III locally advanced rectal cancer from 35 German institutions. Patients in the capecitabine group were scheduled to receive two cycles of capecitabine (2500 mg/m2 days 1–14, repeated day 22), followed by chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m2 days 1–38), then three cycles of capecitabine. Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m2 days 1–5, repeated day 29), followed by chemoradiotherapy (50·4 Gy plus infusional fluorouracil 225 mg/m2 daily), then two cycles of bolus fluorouracil. The protocol was amended in March, 2005, to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m2 daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m2 per day for 14 days) and patients in the fluorouracil group received chemoradiotherapy (50·4 Gy plus infusional fluorouracil 1000 mg/m2 days 1–5 and 29–33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m2 for 5 days). Patients were randomly assigned to treatment group in a 1:1 ratio using permuted blocks, with stratification by centre and tumour stage. The primary endpoint was overall survival; analyses were done based on all patients with post-randomisation data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12·5% margin. This trial is registered with ClinicalTrials.gov , number NCT01500993. Findings Between March, 2002, and December, 2007, 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the fluorouracil group), with a median follow-up of 52 months (IQR 41–72). 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group (76% 95% CI 67–82 vs 67% 58–74; p=0·0004; post-hoc test for superiority p=0·05). 3-year disease-free survival was 75% (95% CI 68–81) in the capecitabine group and 67% (59–73) in the fluorouracil group (p=0·07). Similar numbers of patients had local recurrences in each group (12 6% in the capecitabine group vs 14 7% in the fluorouracil group, p=0·67), but fewer patients developed distant metastases in the capecitabine group (37 19% vs 54 28%; p=0·04). Diarrhoea was the most common adverse event in both groups (any grade: 104 53% patients in the capecitabine group vs 85 44% in the fluorouracil group; grade 3–4: 17 9% vs four 2%). Patients in the capecitabine group had more hand-foot skin reactions (62 31% any grade, four 2% grade 3–4 vs three 2% any grade, no grade 3–4), fatigue (55 28% any grade, no grade 3–4 vs 29 15%, two 1% grade 3–4), and proctitis (31 16% any grade, one <1% grade 3–4 vs ten 5%, one <1% grade 3–4) than did those in the fluorouracil group, whereas leucopenia was more frequent with fluorouracil than with capecitabine (68 35% any grade, 16 8% grade 3–4 vs 50 25% any grade, three 2% grade 3–4). Interpretation Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer. Funding Roche Pharma AG (Grenzach-Wyhlen, Germany).
Adjuvant imatinib administered for 12 months after surgery has improved recurrence-free survival (RFS) of patients with operable gastrointestinal stromal tumor (GIST) compared with placebo.
To ...investigate the role of imatinib administration duration as adjuvant treatment of patients who have a high estimated risk for GIST recurrence after surgery.
Patients with KIT-positive GIST removed at surgery were entered between February 2004 and September 2008 to this randomized, open-label phase 3 study conducted in 24 hospitals in Finland, Germany, Norway, and Sweden. The risk of GIST recurrence was estimated using the modified National Institutes of Health Consensus Criteria.
Imatinib, 400 mg per day, orally for either 12 months or 36 months, started within 12 weeks of surgery.
The primary end point was RFS; the secondary end points included overall survival and treatment safety.
Two hundred patients were allocated to each group. The median follow-up time after randomization was 54 months in December 2010. Diagnosis of GIST was confirmed in 382 of 397 patients (96%) in the intention-to-treat population at a central pathology review. KIT or PDGFRA mutation was detected in 333 of 366 tumors (91%) available for testing. Patients assigned for 36 months of imatinib had longer RFS compared with those assigned for 12 months (hazard ratio HR, 0.46; 95% CI, 0.32-0.65; P < .001; 5-year RFS, 65.6% vs 47.9%, respectively) and longer overall survival (HR, 0.45; 95% CI, 0.22-0.89; P = .02; 5-year survival, 92.0% vs 81.7%). Imatinib was generally well tolerated, but 12.6% and 25.8% of patients assigned to the 12- and 36-month groups, respectively, discontinued imatinib for a reason other than GIST recurrence.
Compared with 12 months of adjuvant imatinib, 36 months of imatinib improved RFS and overall survival of GIST patients with a high risk of GIST recurrence.
clinicaltrials.gov Identifier: NCT00116935.
The flood risk management plan challenges both water engineers and spatial planners. It calls for a new mode of governance for flood risk management. This contribution analyses how this mode of ...governance distinguishes from prevalent approaches. Spatial planning and water management in Europe are explored in terms of their actor relation, their institutional context, and their approach to the object. These three characteristics of the modes of governance are compared with the governance requirements that flood risk management demands. It is concluded that the governance of flood risk management in Europe should strike a balance between comprehensive and hierarchical planning on the one hand, and interactive planning on the other hand, leading to a spatial water governance.
The randomized phase II OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) study showed that tumor KRAS mutation status was predictive for outcome in patients ...receiving cetuximab plus FOLFOX-4 (oxaliplatin/5-fluorouracil/folinic acid) as first-line therapy for metastatic colorectal cancer (mCRC).
The biomarker analysis was extended through the use of additional DNA samples extracted from stained tissue sections. KRAS and BRAF tumor mutation status was determined for new (and for BRAF, existing) samples using a PCR technique. Clinical outcome was reassessed according to mutation status. Overall survival data are presented.
Of 315 KRAS evaluable patient samples (93%), 179 tumors (57%) were KRAS wild type. Eleven of 309 (4%) KRAS/BRAF evaluable tumors (all KRAS wild type) carried BRAF mutations. The addition of cetuximab to FOLFOX-4 significantly improved progression-free survival (hazard ratio 0.567, P = 0.0064) and response (odds ratio 2.551, P = 0.0027) in patients with KRAS wild-type tumors. A favorable effect on survival was also observed.
These results confirm the efficacy of cetuximab plus FOLFOX-4 in the first-line treatment of patients with KRAS wild-type mCRC and confirm KRAS mutation status as an effective predictive biomarker. The small number of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or prognostic utility of this biomarker.
Three years of adjuvant imatinib therapy are recommended for patients with GI stromal tumor (GIST) with high-risk features, according to survival findings in the Scandinavian Sarcoma Group XVIII/AIO ...(Arbeitsgemeinschaft Internistische Onkologie) trial. To investigate whether the survival benefits have persisted, we performed the second planned analysis of the trial.
Eligible patients had macroscopically completely excised, KIT-positive GIST with a high risk of recurrence, as determined by using the modified National Institutes of Health criteria. After surgery, the patients were randomly assigned to receive imatinib for either 1 or 3 years. The primary objective was recurrence-free survival (RFS), and the secondary objectives included survival.
A total of 400 patients were entered onto this open-label study between February 4, 2004, and September 29, 2008. During a median follow-up of 90 months, 171 recurrences and 69 deaths were detected. Patients assigned to the 3-year group had longer RFS than those assigned to the 1- year group; 5-year RFS was 71.1% versus 52.3%, respectively (hazard ratio HR, 0.60; 95% CI 0.44 to 0.81; P < .001), and survival was 91.9% versus 85.3% (HR, 0.60; 95% CI, 0.37 to 0.97; P = .036). Patients in the 3-year group survived longer in the subset with centrally confirmed GIST and without macroscopic metastases at study entry (93.4% v 86.8%; HR, 0.53; 95% CI, 0.30 to 0.93; P = .024). Similar numbers of cardiac events and second cancers were recorded in the groups.
Three years of adjuvant imatinib therapy results in longer survival than 1 year of imatinib. High 5-year survival rates are achievable in patient populations with high-risk GIST.
This randomized study assessed whether the best overall response rate (ORR) of cetuximab combined with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) was superior to that of FOLFOX-4 alone as ...first-line treatment for metastatic colorectal cancer. The influence of KRAS mutation status was investigated.
Patients received cetuximab (400 mg/m(2) initial dose followed by 250 mg/m(2)/wk thereafter) plus FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1, plus leucovorin 200 mg/m(2) and fluorouracil as a 400 mg/m(2) bolus followed by a 600 mg/m(2) infusion during 22 hours on days 1 and 2; n = 169) or FOLFOX-4 alone (n = 168). Treatment was continued until disease progression or unacceptable toxicity. KRAS mutation status was assessed in the subset of patients with assessable tumor samples (n = 233).
The confirmed ORR for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone (46% v 36%). A statistically significant increase in the odds for a response with the addition of cetuximab to FOLFOX-4 could not be established (odds ratio = 1.52; P = .064). In patients with KRAS wild-type tumors, the addition of cetuximab to FOLFOX-4 was associated with a clinically significant increased chance of response (ORR = 61% v 37%; odds ratio = 2.54; P = .011) and a lower risk of disease progression (hazard ratio = 0.57; P = .0163) compared with FOLFOX-4 alone. Cetuximab plus FOLFOX-4 was generally well tolerated.
KRAS mutational status was shown to be a highly predictive selection criterion in relation to the treatment decision regarding the addition of cetuximab to FOLFOX-4 for previously untreated patients with metastatic colorectal cancer.
Summary Background Neoadjuvant chemotherapy for unresectable colorectal liver metastases can downsize tumours for curative resection. We assessed the effectiveness of cetuximab combined with ...chemotherapy in this setting. Methods Between Dec 2, 2004, and March 27, 2008, 114 patients were enrolled from 17 centres in Germany and Austria; three patients receiving FOLFOX6 alone were excluded from the analysis. Patients with non-resectable liver metastases (technically non-resectable or ≥5 metastases) were randomly assigned to receive cetuximab with either FOLFOX6 (oxaliplatin, fluorouracil, and folinic acid; group A) or FOLFIRI (irinotecan, fluorouracil, and folinic acid; group B). Randomisation was not blinded, and was stratified by technical resectability and number of metastases, use of PET staging, and EGFR expression status. They were assessed for response every 8 weeks by CT or MRI. A local multidisciplinary team reassessed resectability after 16 weeks, and then every 2 months up to 2 years. Patients with resectable disease were offered liver surgery within 4–6 weeks of the last treatment cycle. The primary endpoint was tumour response assessed by Response Evaluation Criteria In Solid Tumours (RECIST), analysed by modified intention to treat. A retrospective, blinded surgical review of patients with radiological images at both baseline and during treatment was done to assess objectively any changes in resectability. The study is registered with ClinicalTrials.gov , number NCT00153998. Findings 56 patients were randomly assigned to group A and 55 to group B. One patient in each group were excluded from the analysis of the primary endpoint because they discontinued treatment before first full dose, one patient in group B was excluded because of early pulmonary embolism. A confirmed partial or complete response was noted in 36 (68%) of 53 patients in group A, and 30 (57%) of 53 patients in group B (difference 11%, 95% CI −8 to 30; odds ratio OR 1·62, 0·74–3·59; p=0·23). The most frequent grade 3 and 4 toxicities were skin toxicity (15 of 54 patients in group A, and 22 of 55 patients in group B), and neutropenia (13 of 54 patients in group A and 12 of 55 patients in group B). R0 resection was done in 20 (38%) of 53 patients in group A and 16 (30%) of 53 of patients in group B. In a retrospective analysis of response by KRAS status, a partial or complete response was noted in 47 (70%) of 67 patients with KRAS wild-type tumours versus 11 (41%) of 27 patients with KRAS -mutated tumours (OR 3·42, 1·35–8·66; p=0·0080). According to the retrospective review, resectability rates increased from 32% (22 of 68 patients) at baseline to 60% (41 of 68) after chemotherapy (p<0·0001). Interpretation Chemotherapy with cetuximab yields high response rates compared with historical controls, and leads to significantly increased resectability. Funding Merck-Serono, Sanofi-Aventis, and Pfizer.
Organophosphate insecticides such as chlorpyrifos are commonly detected in surface waters around the world, where they are highly toxic to many organisms. The frog Physalaemus gracilis uses water ...sources located in open fields as reproductive sites, where it is exposed to insecticides. The study aimed to evaluate the lethal and sublethal effect of a commercial chlorpyrifos formulation on P. gracilis tadpoles (Anura: Leptodactylidae). In acute toxicity tests, five chlorpyrifos concentrations between 750 and 2,000 μg L−1 were tested. Chronic toxicity, swimming activity, morphological and enzymatic changes, as well as levels of non-protein thiols (NPSH), carbonyl proteins and lipid peroxidation were evaluated at five insecticide concentrations between 11 and 500 μg L−1. The highest mortality rate of P. gracilis tadpoles occurred at 24 and 48 h, with an LC50 of 893.59 μg L−1. At all chlorpyrifos concentrations, tadpoles displayed reduced mobility and spasms. Morphological anomalies were observed in the mouth and intestine, especially at the highest concentrations used. Acetylcholinesterase activity decreased at 250 and 500 μg L−1, catalase activity increased at all concentrations, and superoxide dismutase and glutathione S-transferase increased from 90 μg L−1 to 30 μg L−1, respectively. We also observed increases in NPSH levels at chlorpyrifos concentration starting at 30 μg L−1 and increases in carbonyl proteins from 90 μg L−1 of pesticide. Taken together, these data suggest that the insecticide chlorpyrifos presents acute and chronic risks for P. gracilis, causing neurotoxic effects and oxidative damage, culminating in high risk for this species.
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•Chlorpyrifos affected swimming activity in P. gracilis.•Mouth and intestine malformations were observed in chlorpyrifos-treated P. gracilis.•Biochemical changes are good biomarkers of chlorpyrifos.•The insecticide chlorpyrifos presented acute and chronic risks to P. gracilis.•P. gracilis is a potential bioindicator of the action of chlorpyrifos.
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