Quantification in cardiovascular magnetic resonance: agreement of software from three different vendors on assessment of left ventricular function, 2D flow and parametric mapping.

BACKGROUND: Quantitative results of cardiovascular magnetic resonance (CMR) image analysis influence clinical decision making. Image analysis is performed based on dedicated software. The manufacturers provide different analysis tools whose algorithms are often unknown. The aim of this study was to evaluate the impact of software on quantification of left ventricular (LV) assessment, 2D flow measurement and T1- and T2-parametric mapping. METHODS: Thirty-one data sets of patients who underwent a CMR Scan on 1.5 T were analyzed using three different software (Circle CVI: cvi42, Siemens Healthineers: Argus, Medis: Qmass/Qflow) by one reader blinded to former results. Cine steady state free precession short axis images were analyzed regarding LV ejection fraction (EF), end-systolic and end-diastolic volume (ESV, EDV) and LV mass. Phase-contrast magnetic resonance images were evaluated for forward stroke volume (SV) and peak velocity (Vmax). Pixel-wise generated native T1- and T2-maps were used to assess T1- and T2-time. Forty-five data sets were evaluated twice (15 per software) for intraobserver analysis. Equivalence was considered if the confidence interval of a paired assessment of two sofware was within a tolerance interval defined by ±1.96 highest standard deviation obtained by intraobserver analysis. RESULTS: For each parameter, thirty data sets could be analyzed with all three software. All three software (A/B, A/C, B/C) were considered equivalent for LV EF, EDV, ESV, mass, 2D flow SV and T2-time. Differences between software were detected in flow measurement for Vmax and in parametric mapping for T1-time. For Vmax, equivalence was given between software A and C and for T1-time equivalence was given between software B and C. CONCLUSION: Software had no impact on quantitative results of LV assessment, T2-time and SV based on 2D flow. In contrast to that, Vmax and T1-time may be influenced by software. CMR reports should contain the name and version of the software applied for image analysis to avoid misinterpretation upon follow-up and research examinations. TRIAL REGISTRATION: ISRCTN12210850 . Registered 14 July 2017, retrospectively registered.

Comparison of fast multi-slice and standard segmented techniques for detection of late gadolinium enhancement in ischemic and non-ischemic cardiomyopathy - a prospective clinical cardiovascular magnetic resonance trial.

BACKGROUND: Segmented phase-sensitive inversion recovery (PSIR) cardiovascular magnetic resonance (CMR) sequences are reference standard for non-invasive evaluation of myocardial fibrosis using late gadolinium enhancement (LGE). Several multi-slice LGE sequences have been introduced for faster acquisition in patients with arrhythmia and insufficient breathhold capability. The aim of this study was to assess the accuracy of several multi-slice LGE sequences to detect and quantify myocardial fibrosis in patients with ischemic and non-ischemic myocardial disease. METHODS: Patients with known or suspected LGE due to chronic infarction, inflammatory myocardial disease and hypertrophic cardiomyopathy (HCM) were prospectively recruited. LGE images were acquired 10-20 min after administration of 0.2 mmol/kg gadolinium-based contrast agent. Three different LGE sequences were acquired: a segmented, single-slice/single-breath-hold fast low angle shot PSIR sequence (FLASH-PSIR), a multi-slice balanced steady-state free precession inversion recovery sequence (bSSFP-IR) and a multi-slice bSSFP-PSIR sequence during breathhold and free breathing. Image quality was evaluated with a 4-point scoring system. Contrast-to-noise ratios (CNR) and acquisition time were evaluated. LGE was quantitatively assessed using a semi-automated threshold method. Differences in size of fibrosis were analyzed using Bland-Altman analysis. RESULTS: Three hundred twelve patients were enrolled (n = 212 chronic infarction, n = 47 inflammatory myocardial disease, n = 53 HCM) Of which 201 patients (67,4%) had detectable LGE (n = 143 with chronic infarction, n = 27 with inflammatory heart disease and n = 31 with HCM). Image quality and CNR were best on multi-slice bSSFP-PSIR. Acquisition times were significantly shorter for all multi-slice sequences (bSSFP-IR: 23.4 ± 7.2 s; bSSFP-PSIR: 21.9 ± 6.4 s) as compared to FLASH-PSIR (361.5 ± 95.33 s). There was no significant difference of mean LGE size for all sequences in all study groups (FLASH-PSIR: 8.96 ± 10.64 g; bSSFP-IR: 8.69 ± 10.75 g; bSSFP-PSIR: 9.05 ± 10.84 g; bSSFP-PSIR free breathing: 8.85 ± 10.71 g, p > 0.05). LGE size was not affected by arrhythmia or absence of breathhold on multi-slice LGE sequences. CONCLUSIONS: Fast multi-slice and standard segmented LGE sequences are equivalent techniques for the assessment of myocardial fibrosis, independent of an ischemic or non-ischemic etiology. Even in patients with arrhythmia and insufficient breathhold capability, multi-slice sequences yield excellent image quality at significantly reduced scan time and may be used as standard LGE approach. TRIAL REGISTRATION: ISRCTN48802295 (retrospectively registered).

In vivo evaluation of tumor uptake and bio-distribution of 99mTc-labeled 1-thio-ß-D-glucose and 5-thio-D-glucose in mice model.

BACKGROUND: To investigate the capacity of 99mTc-labeled 1-thio-ß-D-glucose (1-TG) and 5-thio-D-glucose (5-TG) to act as a marker for glucose consumption in tumor cells in vivo as well as to evaluate the biodistribution of 1-TG and 5-TG. We investigated the biodistribution, including tumor uptake, of 1-TG and 5-TG at various time points after injection (0.5, 2 and 4 h) in human colorectal carcinoma (HCT-116) and human lung adenocarcinoma (A549) xenograft bearing nude mice (N = 4 per tracer and time point). RESULTS: Ex vivo biodistribution studies revealed a moderate uptake with a maximum tumor-to-muscle ratio of 4.22 ± 2.7 and 2.2 ± 1.3 (HCT-116) and of 3.2 ± 1.1 and 4.1 ± 1.3 (A549) for 1-TG and 5-TG, respectively, with a peak at 4 h for 1-TG and 5-TG. Biodistribution revealed a significantly higher uptake compared to blood in kidneys (12.18 ± 8.77 and 12.69 ± 8.93%ID/g at 30 min) and liver (2.6 ± 2.8%ID/g) for 1-TG and in the lung (7.24 ± 4.1%ID/g), liver (6.38 ± 2.94%ID/g), and kidneys (4.71 ± 1.97 and 4.81 ± 1.91%ID/g) for 5-TG. CONCLUSIONS: 1-TG and 5-TG showed an insufficient tumor uptake with a moderate tumor-to-muscle ratio, not reaching the levels of commonly used tracer, for diagnostic use in human colorectal carcinoma and human lung adenocarcinoma xenograft model.

Early myocardial oedema can predict subsequent cardiomyopathy in high-dose anthracycline therapy.

AIMS: This study aims to assess subclinical changes in functional and morphologic myocardial MR parameters very early into a repetitive high-dose anthracycline treatment (planned cumulative dose >650 mg/m2 ), which may predict subsequent development of anthracycline-induced cardiomyopathy (aCMP). METHODS: Thirty sarcoma patients with previous exposition of 300-360 mg/m2 doxorubicin-equivalent chemotherapy who were planned for a second treatment of anthracycline-based chemotherapy (360 mg/m2 doxorubicin-equivalent) were recruited. Enrolled individuals received three CMR studies (before treatment, 48 h after first anthracycline treatment and upon completion of treatment). Native T1 mapping (MOLLI 5s(3s)3s), T2 mapping, and extracellular volume (ECV) maps were acquired in addition to a conventional CMR with SSFP-cine imaging at 1.5 T. Patients were given 0.2 mmol/kg gadoteridol for ECV quantification and LGE imaging. Blood samples for cardiac biomarkers were obtained before each scan. Development of relevant aCMP was defined as drop of left ventricular ejection fraction (LVEF) by >10% compared with baseline. RESULTS: Twenty-three complete datasets were available for analysis. Median treatment time was 20.7 ± 3.0 weeks. Eight patients developed aCMP with LVEF reduction >10% until end of chemotherapy. Baseline LVEF was not different between patients with and without subsequent aCMP. Patients with aCMP had decreased LV mass upon completion of therapy (99.4 ± 26.5 g vs. 90.3 ± 24.8 g; P = 0.02), whereas patients without aCMP did not show a change in LV mass (91.5 ± 20.0 g vs. 89.0 ± 23.6 g; P > 0.05). On strain analysis, GLS (-15.3 ± 1.3 vs. -13.4 ± 1.6; P = 0.02) and GCS (-16.7 ± 2.1 vs. -14.9 ± 2.6; P = 0.04) were decreased in aCMP patients upon completion of therapy, whereas non-aCMP individuals showed no change in GLS (-15.4 ± 3.3 vs. -15.4 ± 3.4; P = 0.97). When assessed 48 h after first dose of anthracyclines, patients with subsequent aCMP had significantly elevated myocardial T2 times compared with before therapy (53.0 ± 2.8 ms vs. 49.3 ± 5.2 ms, P = 0.02) than patients who did not develop aCMP (50.7 ± 5.1 ms vs. 51.1 ± 3.9 ms, P > 0.05). Native T1 times decreased at 48 h after first dose irrespective of development of subsequent aCMP (1020.2 ± 28.4 ms vs. 973.5 ± 40.3 ms). Upon completion of therapy, patients with aCMP had increased native T1 compared with baseline (1050.8 ± 17.9 ms vs. 1022.4 ± 22.0 ms; P = 0.01), whereas non-aCMP patients did not (1034.5 ± 46.6 ms vs. 1018.4 ± 29.7 ms; P = 0.15). No patient developed new myocardial scars or compact myocardial fibrosis under chemotherapy. Cardiac biomarkers were elevated independent of development of aCMP. CONCLUSIONS: With high cumulative anthracycline doses, early increase of T2 times 48 h after first treatment with anthracyclines can predict the development of subsequent aCMP after completion of chemotherapy. Early drop of native T1 times occurs irrespective of development of aCMP in high-dose anthracycline therapy.

Characterization of critically ill patients with septic shock and sepsis-associated cardiomyopathy using cardiovascular MRI.

AIMS: Sepsis-induced cardiomyopathy is a major complication of septic shock and contributes to its high mortality. This pilot study investigated myocardial tissue differentiation in critically ill, sedated, and ventilated patients with septic shock using cardiovascular magnetic resonance (MR). METHODS AND RESULTS: Fifteen patients with septic shock were prospectively recruited from the intensive care unit. Individuals received a cardiac MR scan (1.5 T) within 48 h after initial catecholamine peak and a transthoracic echocardiography at 48 and 96 h after cardiac MR. Left ventricular ejection fraction was assessed using both imaging modalities. During cardiac MR imaging, balanced steady-state free precession imaging was performed for evaluation of cardiac anatomy and function in long-axis and short-axis views. Native T1 maps (modified Look-Locker inversion recovery 5 s(3 s)3 s), T2 maps, and extracellular volume maps were acquired in mid-ventricular short axis and assessed for average plane values. Patients were given 0.2 mmol/kg of gadoteridol for extracellular volume quantification and late gadolinium enhancement imaging. Critical care physicians monitored sedated and ventilated patients during the scan with continuous invasive monitoring and realized breathholds through manual ventilation breaks. Laboratory analysis included high-sensitive troponine T and N terminal pro brain natriuretic peptide levels. Twelve individuals with complete datasets were available for analysis (age 59.5 ± 16.9 years; 6 female). Nine patients had impaired systolic function with left ventricular ejection fraction (LVEF) < 50% (39.8 ± 5.7%), and three individuals had preserved LVEF (66.9 ± 6.7%). Global longitudinal strain was impaired in both subgroups (LVEF impaired: 11.0 ± 1.8%; LVEF preserved: 16.0 ± 5.8%; P = 0.1). All patients with initially preserved LVEF died during hospital stay; in-hospital mortality with initially impaired LVEF was 11%. Upon echocardiographic follow-up, LVEF improved in all previously impaired patients at 48 (52.3 ± 9.0%, P = 0.06) and 96 h (54.9 ± 7.0%, P = 0.02). Patients with impaired systolic function had increased T2 times as compared with patients with preserved LVEF (60.8 ± 5.6 ms vs. 52.2 ± 2.8 ms; P = 0.02). Left ventricular GLS was decreased in all study individuals with impaired LVEF (11.0 ± 1.8%) and less impaired with preserved LVEF (16.0 ± 5.8%; P = 0.01). T1 mapping showed increased T1 times in patients with LVEF impairment as compared with patients with preserved LVEF (1093.9 ± 86.6 ms vs. 987.7 ± 69.3 ms; P = 0.03). Extracellular volume values were elevated in patients with LVEF impairment (27.9 ± 2.1%) as compared with patients with preserved LVEF (22.7 ± 1.9%; P < 0.01). CONCLUSIONS: Septic cardiomyopathy with impaired LVEF reflects inflammatory cardiomyopathy. Takotsubo-like contractility patterns occur in some cases. Cardiac MR is safely feasible in critically ill, sedated, and ventilated patients using extensive monitoring and experienced staff. TRIAL REGISTRATION: retrospectively registered (ISRCTN85297773).

Adipose tissue-derived stem cells promote prostate tumor growth.

BACKGROUND: Recent evidence indicates that cancer stem cells play an important role in tumor initiation and maintenance. Additionally, the effect of tissue-resident stem cells located in the surrounding healthy tissue on tumor progression has been demonstrated. While most knowledge has been derived from studies of breast cancer cells, little is known regarding the influence of tissue resident stem cells on the tumor biology of prostate cancer. METHODS: Twenty male athymic Swiss nu/nu mice (age: 6-8 weeks) were randomized into two treatment groups: (1) subcutaneous injection of 10(6) MDA PCa 118b human prostate cancer cells into the upper back or (2) subcutaneous injection of 10(6) MDA PCa 118b cells mixed directly with 10(5) GFP-labeled human adipose tissue-derived stem cells (hASCs). Tumor growth and volumes over the ensuing 3 weeks were assessed using calipers and micro-computed tomography. Immunohistochemistry was performed to identify engrafted hASCs in tumor sections. RESULTS: At 3 weeks after injection, the mean tumor volume in the MDA PCa 118b/hASC co-injection group (1019.95 ± 73.49 mm(3)) was significantly higher than that in the MDA PCa 118b-only group (308.70 ± 21.06 mm(3)). Engrafted hASCs exhibited the nuclear marker of proliferation Ki67 and expressed markers for endothelial differentiation, indicating their engraftment in tumor vessels. CONCLUSION: Our study revealed for the first time that ASCs subcutaneously co-injected with prostate cancer cells engraft and promote tumor progression. Further evaluation of the cross-talk between tumor and local tissue-resident stem cells may lead to new strategies for prostate cancer therapy.

Comparability of compressed sensing-based gradient echo perfusion sequence SPARSE and conventional gradient echo sequence in assessment of myocardial ischemia.

PURPOSE: Stress perfusion imaging plays a major role in non-invasive detection of coronary artery disease. We compared a compressed sensing-based and a conventional gradient echo perfusion sequence with regard to image quality and diagnostic performance. METHOD: Patients sent for coronary angiography due to pathologic stress perfusion CMR were recruited. All patients underwent two adenosine stress CMR using conventional TurboFLASH and prototype SPARSE sequence as well as quantitative coronary angiography with fractional flow reserve (FFR) within 6 weeks. Coronary angiography was considered gold standard with FFR < 0.75 or visual stenosis >90 % for identification of myocardial ischemia. Diagnostic performance of perfusion imaging was assessed in basal, mid-ventricular and apical slices by quantification of myocardial perfusion reserve (MPR) analysis utilizing the signal upslope method and a deconvolution technique using the fermi function model. RESULTS: 23 patients with mean age of 69.6 ± 8.9 years were enrolled. 46 % were female. Image quality was similar in conventional TurboFLASH sequence and SPARSE sequence (2.9 ± 0.5 vs 3.1 ± 0.7, p = 0,06). SPARSE sequence showed higher contrast-to-noise ratio (52.1 ± 27.4 vs 40.5 ± 17.6, p < 0.01) and signal-to-noise ratio (15.6 ± 6.2 vs 13.2 ± 4.2, p < 0.01) than TurboFLASH sequence. Dark-rim artifacts occurred less often with SPARSE (9 % of segments) than with TurboFLASH (23 %). In visual assessment of perfusion defects, SPARSE sequence detected less false-positive perfusion defects (n = 1) than TurboFLASH sequence (n = 3). Quantitative perfusion analysis on segment basis showed equal detection of perfusion defects for TurboFLASH and SPARSE with both upslope MPR analysis (TurboFLASH 0.88 ± 0.18; SPARSE 0.77 ± 0.26; p = 0.06) and fermi function model (TurboFLASH 0.85 ± 0.24; SPARSE 0.76 ± 0.30; p = 0.13). CONCLUSIONS: Compressed sensing perfusion imaging using SPARSE sequence allows reliable detection of myocardial ischemia.

Tissue-resident stem cells promote breast cancer growth and metastasis.

Mesenchymal stem cells derived from bone marrow have recently been described to localize to breast carcinomas and to integrate into the tumor-associated stroma. In the present study, we investigated whether adipose tissue-derived stem cells (ASCs) could play a role in tumor growth and invasion. Compared with bone marrow-derived cells, ASCs as tissue-resident stem cells are locally adjacent to breast cancer cells and may interact with tumor cells directly. Here, we demonstrate that ASCs cause the cancer to grow significantly faster when added to a murine breast cancer 4T1 cell line. We further show that breast cancer cells enhance the secretion of stromal cell-derived factor-1 from ASCs, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. The tumor-promoting effect of ASCs was abolished by knockdown of the chemokine C-X-C receptor 4 in 4T1 tumor cells. We demonstrated that ASCs home to tumor site and promote tumor growth not only when co-injected locally but also when injected intravenously. Furthermore, we demonstrated that ASCs incorporate into tumor vessels and differentiate into endothelial cells. The tumor-promoting effect of tissue-resident stem cells was also tested and validated using a human breast cancer line MDA-MB-231 cells and human adipose tissue-derived stem cells. Our findings indicate that the interaction of local tissue-resident stem cells with tumor stem cells plays an important role in tumor growth and metastasis.

Thrombin peptide (TP508) promotes adipose tissue-derived stem cell proliferation via PI3 kinase/Akt pathway.

A synthetic peptide representing the receptor-binding domain of human thrombin (TP508) promotes angiogenesis and accelerates wound healing in animal models. However, the mechanisms underlying the therapeutic effects of TP508 have not been clearly defined. In this study, we set out to determine whether TP508 could stimulate stem cell proliferation. Adipose tissue-derived stem cells (ASCs) were incubated with TP508 (5 microg/ml) and cell proliferation was determined by bromodeoxyuridine (BrdU) incorporation. Our data showed that TP508 treatment significantly stimulated BrdU incorporation in ASCs (p < 0.01). The increased BrdU incorporation induced by TP508 was abolished by the PI3 kinase (PI3K) inhibitor LY294002 at 50 microM. Western blot analysis of ASCs revealed increased phosphorylation of Akt in response to TP508 when compared to unstimulated controls. These results indicate that TP508 exerts proliferative effects on ASCs via the PI3K/Akt pathway.

TNFalpha protects tissue resident stem cells from H2O2 induced apoptosis through a novel NF-small ka, CyrillicB p50/p50 homodimer mediated signaling pathway.

The objective of our study was to determine whether TNFalpha can protect tissue resident stem cells from hydrogen peroxide (H(2)O(2)) induced apoptosis. Apoptosis was measured via fluorescence activated flow cytometry of fluorescein-conjugated Annexin V in passage 3 human ASCs. Our data show that application of 300muM H(2)O(2) for 3h induced a high number of cells to undergo apoptosis. The number of apoptotic cells significantly decreased when cells were preincubated with TNFalpha. TNFalpha caused a rapid activation of NF-kappaB within 15min as evidenced by gel shift assay (EMSA). On further dissection of the NF-small ka, CyrillicB complex, the p50 subunit which generally forms heterodimers with p65 appears to form a p50/p50 homodimer instead of conventional p50/p65 heterodimer. This novel finding has implications for tissue regeneration and might as well be of importance for cancer cell growth and tumor progression.

Native myocardial T1 time can predict development of subsequent anthracycline-induced cardiomyopathy.

AIMS: This study aims to assess subclinical changes in functional and morphological myocardial magnetic resonance parameters very early into an anthracycline treatment, which may predict subsequent development of anthracycline-induced cardiomyopathy (aCMP). METHODS AND RESULTS: Thirty sarcoma patients with planned anthracycline-based chemotherapy (360-400 mg/m2 doxorubicin-equivalent) were recruited. Median treatment time was 19.1 ± 2.1 weeks. Enrolled individuals received three cardiovascular magnetic resonance studies (before treatment, 48 h after first anthracycline treatment, and upon completion of treatment). Native T1 mapping (modified Look-Locker inversion recovery 5s(3s)3s), T2 mapping, and extracellular volume maps were acquired in addition to a conventional cardiovascular magnetic resonance with steady-state free precession cine imaging at 1.5 T. Patients were given 0.2 mmol/kg gadoteridol for extracellular volume quantification and late gadolinium enhancement imaging. Development of relevant aCMP was defined as drop of left ventricular ejection fraction (LVEF) by >10%. For analysis, 23 complete data sets were available. Nine patients developed aCMP with LVEF reduction >10% until end of chemotherapy. Baseline LVEF was not different between patients with and without subsequent aCMP. When assessed 48 h after first dose of antracyclines, patients with subsequent aCMP had significantly lower native myocardial T1 times compared with before therapy (1002.0 ± 37.9 vs. 956.5 ± 29.2 ms, P < 0.01) than patients who did not develop aCMP (990.9 ± 56.4 vs. 978.4 ± 57.4 ms, P > 0.05). Patients with aCMP had decreased left ventricular mass upon completion of therapy (86.9 ± 24.5 vs. 81.1 ± 22.3 g; P = 0.02), while patients without aCMP did not show a change in left ventricular mass (81.8 ± 21.0 vs. 79.2 ± 18.1 g; P > 0.05). No patient developed new myocardial scars or compact myocardial fibrosis under chemotherapy. CONCLUSIONS: Early decrease of T1 times 48 h after first treatment with anthracyclines can predict the development of subsequent aCMP after completion of chemotherapy.

Magnetic Resonance Imaging Applications on Infiltrative Cardiomyopathies.

Infiltrative cardiomyopathies are a heterogenous group of diseases that typically lead to restrictive cardiac dysfunction. Due to similar phenotypes, accurate diagnosis is challenging without invasive endomyocardial biopsy which has historically been considered mandatory. Cardiac magnetic resonance (CMR) has been well established in the diagnostic workup of patients with suspected cardiomyopathies due to its unique capability for tissue differentiation and its unsurpassed accuracy in defining cardiac morphology and function. The increasing variety of CMR techniques has generated both excitement and uncertainty with regard to their potential clinical use and its role vis-à-vis conventional noninvasive imaging techniques. The purpose of this review is to give an overview of established and emerging CMR techniques and typical image characteristics of the most commonly encountered infiltrative cardiomyopathies.

A multicenter cardiovascular MR network for tele-training and beyond: setup and initial experiences.

PURPOSE: Training in cardiovascular MR (CMR) is an important topic in times of growing acceptance of the method for accurate diagnosis and management of cardiovascular disease. However, off-site training is becoming less acceptable with increasing cost and time pressures. We introduce a novel CMR network, capable of providing, remotely, part of CMR training and continuous expert support. By providing a technical and operational blueprint, we want to share our experience in building teaching networks. METHODS: Conceptual, technical, and content-related characteristics of our teaching methods are introduced. A total of 97 participants in traditional fellowship CMR teaching and novel module-based network teaching were surveyed to assess their CMR performance. RESULTS: The number of hospitals in our CMR network increased from five in 2009 to 14 in 2014. A total of 79% of network hospitals conducted >100 CMR scans annually. Among these network hospitals are four small institutions (<400 beds), and five medium-sized hospitals (400-1,000 beds). Network teaching reduced off-site training to only five weeks. The time to the first independently conducted CMR scans was one week, with network teaching, but >1 month for 32% of participants in traditional CMR teaching. The CMR network enables experts from distant locations to supervise and control CMR scans in a distant hospital, in real time. CONCLUSIONS: CMR networks provide an efficient teaching platform with a minimum of off-site time for trainees. Real-time remote supervision and scan control capabilities support the decentralization of CMR expertise and enables even small and rurally located institutions to offer high-quality CMR scans.

Wound microenvironment sequesters adipose-derived stem cells in a murine model of reconstructive surgery in the setting of concurrent distant malignancy.

BACKGROUND: It is unclear whether mesenchymal stem cells that are applied to regenerate wound tissues can migrate to existing tumors and enhance their growth. The authors investigated whether adipose-derived stem cells had any effect on the growth and progression of distant tumors when applied to a skin wound. METHODS: The authors subcutaneously injected murine 4T1 breast cancer cells into all BALB/c-nu/nu mice. After tumor injection, mice were randomized to five groups (five mice per group) based on the means of co-introduction of green fluorescent protein-labeled adipose-derived stem cells, if any. In group 1, adipose-derived stem cells were combined and co-injected subcutaneously. In group 2, they were injected subcutaneously at a distant anatomical site. In group 3, they were injected intravenously. In group 4, they were delivered via a human acellular dermal matrix to a distant skin wound. In group 5, no adipose-derived stem cells were introduced. RESULTS: After 2 weeks, tumor volume increased in group 1 (356.5 ± 44.4 mm(3)), followed by group 3 (256.6 ± 47.1 mm(3)) and then group 2 (201.6 ± 28.6 mm(3)). In group 4, in which adipose-derived stem cells carried on acellular dermal matrix were applied to a wound distant to the primary tumor, the tumor volume was 143.8 ± 50.9 mm(3), which was similar to that observed in the control group (group 5; 167.8 ± 29.9 mm(3)). CONCLUSIONS: The authors' findings suggest that the wound microenvironment can retain adipose-derived stem cells, preventing their homing and stromal contribution to a distant neoplastic focus. These findings are an important first step in establishing the feasibility and safety of utilizing adipose-derived stem cell therapy for reconstructive surgery in the setting of malignancy.

CXCR4 receptor positive spheroid forming cells are responsible for tumor invasion in vitro.

Stem cells have been found to be involved in breast cancer growth, but the specific contribution of cancer stem cells in tumor biology, including metastasis, is still uncertain. We found that murine breast cancer cell lines 4T1, 4TO7, 167Farn and 67NR contains cancer stem cells defined by CXCR4 expression and their capability of forming spheroids in suspension culture. Importantly, we showed that CXCR4 expression is essential for tumor invasiveness because both CXCR4 neutralizing antibody and shRNA knockdown of the CXCR4 receptor significantly reduced tumor cell invasion.

Tissue resident stem cells produce CCL5 under the influence of cancer cells and thereby promote breast cancer cell invasion.

In the present study, we investigated whether human adipose tissue derived stem cells (hASCs) could enhance tumor invasion and whether these hASCs could be a potential source of CCL5. We observed a significant increase in the number of breast cancer cells that invaded the matrigel when Co-cultured with hASCs. We found that hASCs produce CCL5 in the Co-culture and cancer cell invasion was diminished by an antibody against CCL5. Furthermore, cancer cell invasion in the Co-culture was associated with an elevated level of MMP-9 activity. We conclude that CCL5 plays a crucial role for tumor invasion in the interplay of tissue resident stem cells from the fat tissue and breast cancer cells.