A prospective study on tumour response assessment methods after neoadjuvant endocrine therapy in early oestrogen receptor-positive breast cancer.

BACKGROUND: Neoadjuvant endocrine therapy (NET) in oestrogen receptor-positive (ER+) /HER2-negative (HER2-) breast cancer allows real-time evaluation of drug efficacy as well as investigation of the biological and molecular changes that occur after estrogenic deprivation. Clinical and pathological evaluation after NET may be used to obtain prognostic and predictive information of tumour response to decide adjuvant treatment. In this setting, clinical scales developed to evaluate response after neoadjuvant chemotherapy are not useful and there are not validated biomarkers to assess response to NET beyond Ki67 levels and preoperative endocrine prognostic index score (mPEPI). METHODS: In this prospective study, we extensively analysed radiological (by ultrasound scan (USS) and magnetic resonance imaging (MRI)) and pathological tumour response of 104 postmenopausal patients with ER+ /HER2- resectable breast cancer, treated with NET for a mean of 7 months prior to surgery. We defined a new score, tumour cellularity size (TCS), calculated as the product of the residual tumour cellularity in the surgical specimen and the tumour pathological size. RESULTS: Our results show that radiological evaluation of response to NET by both USS and MRI underestimates pathological tumour size (path-TS). Tumour size [mean (range); mm] was: path-TS 20 (0-80); radiological-TS by USS 9 (0-31); by MRI: 12 (0-60). Nevertheless, they support the use of MRI over USS to clinically assess radiological tumour response (rad-TR) due to the statistically significant association of rad-TR by MRI, but not USS, with Ki67 decrease (p = 0.002 and p = 0.3, respectively) and mPEPI score (p = 0.002 and p = 0.6, respectively). In addition, we propose that TCS could become a new tool to standardize response assessment to NET given its simplicity, reproducibility and its good correlation with existing biomarkers (such as ΔKi67, p = 0.001) and potential added value. CONCLUSION: Our findings shed light on the dynamics of tumour response to NET, challenge the paradigm of the ability of NET to decrease surgical volume and point to the utility of the TCS to quantify the scattered tumour response usually produced by endocrine therapy. In the future, these results should be validated in independent cohorts with associated survival data.

Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer.

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.

C3G Protein, a New Player in Glioblastoma.

C3G (RAPGEF1) is a guanine nucleotide exchange factor (GEF) for GTPases from the Ras superfamily, mainly Rap1, although it also acts through GEF-independent mechanisms. C3G regulates several cellular functions. It is expressed at relatively high levels in specific brain areas, playing important roles during embryonic development. Recent studies have uncovered different roles for C3G in cancer that are likely to depend on cell context, tumour type, and stage. However, its role in brain tumours remained unknown until very recently. We found that C3G expression is downregulated in GBM, which promotes the acquisition of a more mesenchymal phenotype, enhancing migration and invasion, but not proliferation. ERKs hyperactivation, likely induced by FGFR1, is responsible for this pro-invasive effect detected in C3G silenced cells. Other RTKs (Receptor Tyrosine Kinases) are also dysregulated and could also contribute to C3G effects. However, it remains undetermined whether Rap1 is a mediator of C3G actions in GBM. Various Rap1 isoforms can promote proliferation and invasion in GBM cells, while C3G inhibits migration/invasion. Therefore, other RapGEFs could play a major role regulating Rap1 activity in these tumours. Based on the information available, C3G could represent a new biomarker for GBM diagnosis, prognosis, and personalised treatment of patients in combination with other GBM molecular markers. The quantification of C3G levels in circulating tumour cells (CTCs) in the cerebrospinal liquid and/or circulating fluids might be a useful tool to improve GBM patient treatment and survival.

Perceived physical fitness mediates the relationship between parental support and physical activity enjoyment in overweight and obese adolescents.

The relationship between parental support and physical activity enjoyment appears to be mediated by individual-level factors. The aim of this study was to examine whether the relationship between perceived parental support and physical activity enjoyment is mediated by overweight and obese adolescents' physical fitness, both subjectively and objectively assessed. A total of 163 participants (mean age =14.30 years, 55.8% boys) with an average body mass index of 28.97 kg/m2 took part in this study. Participants completed a questionnaire of parental influence regarding physical activity, a questionnaire of physical self-perception and several fitness tests (cardiorespiratory fitness, lower limbs muscular strength and flexibility) using the ALPHA-fitness battery. The results showed that relationship between perceived parental support and physical activity enjoyment is mediated by the overweight and obese adolescents' perceived cardiorespiratory fitness and flexibility. We suggest to create educational guidelines for parents to increase the support and improve overweight and obese students' positive perceived physical competence, in order to achieve a greater adherence to physical activity and greater physical activity enjoyment.

Analysis of the Effect Size of Overweight in Muscular Strength Tests Among Adolescents: Reference Values According to Sex, Age, and Body Mass Index.

Martínez-López, EJ, De La Torre-Cruz, M, Suárez-Manzano, S, and Ruiz-Ariza, A. Analysis of the effect size of overweight in muscular strength tests among adolescents: reference values according to sex, age, and body mass index. J Strength Cond Res 32(5): 1404-1414, 2018-The aim of this paper is to quantify the effect size of overweight on the results of muscular strength tests in adolescents and to report percentile tables based on sex, age, and body mass index (BMI). The study hypothesized that the effect size obtained from the difference between normal-weight and overweight youth would be greater than the differences between sexes within the same age group. A total of 11,044 Spanish adolescents (48.5% girls) aged 14.39 ± 1.21 years (range: 12-16 years) from 42 secondary schools participated in the research. Muscular strength was evaluated using standing long jump, hand grip strength (manual dynamometer), and sit-ups (30 seconds). The effect size was analyzed using the adjusted Hedges' g. The results show that 76.3 and 72.8% of overweight boys and girls, respectively, performed a standing long jump equal to or less than the normal-weight average. The 67.4 and 67.1% of overweight boys and girls, respectively, showed manual dynamometer values equal to or greater than the normal-weight average. Finally, 68.7 and 65.9% of overweight boys and girls, respectively, obtained measures for 30 seconds of sit-ups equal to or lower than the normal-weight average. It can therefore be concluded that the differential effect size between boys and girls is higher than that between normal-weight and overweight adolescents in the 3 strength tests analyzed. Despite the above, these results suggest the value of taking into account the BMI when assessing the muscular strength of young people, in addition to sex and age.

Effects of Physical Activity on Cognition, Behavior, and Motor Skills in Youth with Autism Spectrum Disorder: A Systematic Review of Intervention Studies.

The aim of this paper was to analyze the acute and chronic effects of physical activity (PA) on cognition, behavior, and motor skill in youth with autism spectrum disorder (ASD), taking into account potential confounders. In addition, it was intended to elaborate a guide of educational applications with strategies for PA use. Studies were identified in four databases from January 2010 to June 2023. A total of 19 interventional studies met the inclusion criteria. PA programs ranged from two weeks to one year in duration, with a frequency of one to five sessions per week. More than 58% of the studies showed positive effects of PA on cognition, and 45.5% on behavior and motor skill. Moderate-vigorous PA for 15-30 min has shown acute effects on cognition, general behavior, and stereotypic/repetitive behaviors in youth with ASD. A total of 9 out of 14 studies showed chronic effects on general behavior and stereotypic behaviors, and only 6 on motor skills.

Effect of an Integrated Active Lessons Programme through Playful Maths Games on Self-Concept, Self-Esteem and Social Skills in Preschool Children.

The aim of this study was to analyse the effects of an integrated active lessons programme based on playful math games, of 10 weeks' duration (30 min/day × 2 days/week), on self-concept, self-esteem and social skills in preschool children. One hundred and ninety-four preschool children (53.6% girls) aged 53.36 ± 11.82 months were split into a control group (CG) and an experimental group (EG). The EG improved significantly in self-concept compared to the CG in boys and girls (6.8% and 7.1%, respectively). Personal and academic self-esteem levels increased significantly (8.1% and 5.5%, respectively, only in girls). Although the EG obtained significant improvements in social self-esteem and social skills compared to the beginning of the study, these results were not found in comparison with the CG. The introduction of active lessons based on playful maths games within the classroom is recommended as support for the improvement in self-concept, self-esteem and social skills in early childhood education.

Identification of fatty acid amide hydrolase as a metastasis suppressor in breast cancer.

Clinical management of breast cancer (BC) metastasis remains an unmet need as it accounts for 90% of BC-associated mortality. Although the luminal subtype, which represents >70% of BC cases, is generally associated with a favorable outcome, it is susceptible to metastatic relapse as late as 15 years after treatment discontinuation. Seeking therapeutic approaches as well as screening tools to properly identify those patients with a higher risk of recurrence is therefore essential. Here, we report that the lipid-degrading enzyme fatty acid amide hydrolase (FAAH) is a predictor of long-term survival in patients with luminal BC, and that it blocks tumor progression and lung metastasis in cell and mouse models of BC. Together, our findings highlight the potential of FAAH as a biomarker with prognostic value in luminal BC and as a therapeutic target in metastatic disease.

Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment.

The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression.

HGK promotes metastatic dissemination in prostate cancer.

Metastasis is the process of cancer cell dissemination from primary tumors to different organs being the bone the preferred site for metastatic homing of prostate cancer (PCa) cells. Prostate tumorigenesis is a multi-stage process that ultimately tends to advance to become metastatic PCa. Once PCa patients develop skeletal metastases, they eventually succumb to the disease. Therefore, it is imperative to identify essential molecular drivers of this process to develop new therapeutic alternatives for the treatment of this devastating disease. Here, we have identified MAP4K4 as a relevant gene for metastasis in PCa. Our work shows that genetic deletion of MAP4K4 or pharmacological inhibition of its encoded kinase, HGK, inhibits metastatic PCa cells migration and clonogenic properties. Hence, MAP4K4 might promote metastasis and tumor growth. Mechanistically, our results indicate that HGK depleted cells exhibit profound differences in F-actin organization, increasing cell spreading and focal adhesion stability. Additionally, HGK depleted cells fails to respond to TNF-α stimulation and chemoattractant action. Moreover, here we show that HGK upregulation in PCa samples from TCGA and other databases correlates with a poor prognosis of the disease. Hence, we suggest that it could be used as prognostic biomarker to predict the appearance of an aggressive phenotype of PCa tumors and ultimately, the appearance of metastasis. In summary, our results highlight an essential role for HGK in the dissemination of PCa cells and its potential use as prognostic biomarker.

C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells.

Glioblastoma (GBM) is the most aggressive tumor from the central nervous system (CNS). The current lack of efficient therapies makes essential to find new treatment strategies. C3G, a guanine nucleotide exchange factor for some Ras proteins, plays a dual role in cancer, but its function in GBM remains unknown. Database analyses revealed a reduced C3G mRNA expression in GBM patient samples. C3G protein levels were also decreased in a panel of human GBM cell lines as compared to astrocytes. Based on this, we characterized C3G function in GBM using in vitro and in vivo human GBM models. We report here that C3G downregulation promoted the acquisition of a more mesenchymal phenotype that enhanced the migratory and invasive capacity of GBM cells. This facilitates foci formation in anchorage-dependent and -independent growth assays and the generation of larger tumors in xenografts and chick chorioallantoic membrane (CAM) assays, but with a lower cell density, as proliferation was reduced. Mechanistically, C3G knock-down impairs EGFR signaling by reducing cell surface EGFR through recycling inhibition, while upregulating the activation of several other receptor tyrosine kinases (RTKs) that might promote invasion. In particular, FGF2, likely acting through FGFR1, promoted invasion of C3G-silenced GBM cells. Moreover, ERKs mediate this invasiveness, both in response to FGF2- and serum-induced chemoattraction. In conclusion, our data show the distinct dependency of GBM tumors on C3G for EGF/EGFR signaling versus other RTKs, suggesting that assessing C3G levels may discriminate GBM patient responders to different RTK inhibition protocols. Hence, patients with a low C3G expression might not respond to EGFR inhibitors.

C3G Is Upregulated in Hepatocarcinoma, Contributing to Tumor Growth and Progression and to HGF/MET Pathway Activation.

The complexity of hepatocellular carcinoma (HCC) challenges the identification of disease-relevant signals. C3G, a guanine nucleotide exchange factor for Rap and other Ras proteins, plays a dual role in cancer acting as either a tumor suppressor or promoter depending on tumor type and stage. The potential relevance of C3G upregulation in HCC patients suggested by database analysis remains unknown. We have explored C3G function in HCC and the underlying mechanisms using public patient data and in vitro and in vivo human and mouse HCC models. We found that C3G is highly expressed in progenitor cells and neonatal hepatocytes, whilst being down-regulated in adult hepatocytes and re-expressed in human HCC patients, mouse HCC models and HCC cell lines. Moreover, high C3G mRNA levels correlate with tumor progression and a lower patient survival rate. C3G expression appears to be tightly modulated within the HCC program, influencing distinct cell biological properties. Hence, high C3G expression levels are necessary for cell tumorigenic properties, as illustrated by reduced colony formation in anchorage-dependent and -independent growth assays induced by permanent C3G silencing using shRNAs. Additionally, we demonstrate that C3G down-regulation interferes with primary HCC tumor formation in xenograft assays, increasing apoptosis and decreasing proliferation. In vitro assays also revealed that C3G down-regulation enhances the pro-migratory, invasive and metastatic properties of HCC cells through an epithelial-mesenchymal switch that favors the acquisition of a more mesenchymal phenotype. Consistently, a low C3G expression in HCC cells correlates with lung metastasis formation in mice. However, the subsequent restoration of C3G levels is associated with metastatic growth. Mechanistically, C3G down-regulation severely impairs HGF/MET signaling activation in HCC cells. Collectively, our results indicate that C3G is a key player in HCC. C3G promotes tumor growth and progression, and the modulation of its levels is essential to ensure distinct biological features of HCC cells throughout the oncogenic program. Furthermore, C3G requirement for HGF/MET signaling full activation provides mechanistic data on how it works, pointing out the relevance of assessing whether high C3G levels could identify HCC responders to MET inhibitors.

48-Hour Effects of Monitored Cooperative High-Intensity Interval Training on Adolescent Cognitive Functioning.

Physical activity has been positively related to better cognitive performance though the effects of varied exercise type and intensity and the duration of cognitive benefits are unclear. This study analyzed the effect of 16 minutes of monitored cooperative high-intensity interval training (monitored C-HIIT) at the start of the school day, on various cognitive variables over the next 24-48 hours. We randomly assigned 158 participants either to a control group ( n = 81) that engaged only in static stretching or to an experimental group ( n = 77) that performed monitored C-HIIT. We assessed cognitive functioning before the exercise, immediately afterward, and for five follow-up time points over the next two days (i.e., at 2, 3, 4, 24, and 48 hours). We analyzed age, sex, body mass index, and moderate-to-vigorous physical activity as potential confounder variables. Adolescents in the monitored C-HIIT group increased selective attention by 17.39% during the next hour ( p = .015) and increased concentration by 20.31% and 15.26% during the first ( p = .022) and second ( p = .059) subsequent hours, respectively. This positive short-term benefit of monitored C-HIIT during immediate subsequent hours is an important finding with implications for the school curricula and schedule.

How Rap and its GEFs control liver physiology and cancer development. C3G alterations in human hepatocarcinoma.

Rap proteins regulate liver physiopathology. For example, Rap2B promotes hepatocarcinoma (HCC) growth, while Rap1 might play a dual role. The RapGEF, Epac1, activates Rap upon cAMP binding, regulating metabolism, survival, and liver regeneration. A liver specific Epac2 isoform lacking cAMP-binding domain also activates Rap1, promoting fibrosis in alcoholic liver disease. C3G (RapGEF1) is also present in the liver, but mainly as shorter isoforms. Its function in the liver remains unknown. Information from different public genetic databases revealed that C3G mRNA levels increase in HCC, although they decrease in metastatic stages. In addition, several mutations in RapGEF1 gene are present, associated with a reduced patient survival. Based on this, C3G might represent a new HCC diagnostic and prognostic marker, and a therapeutic target.

Acute and chronic effect of physical activity on cognition and behaviour in young people with ADHD: A systematic review of intervention studies.

BACKGROUND: Young people with attention deficit hyperactivity disorder (ADHD) often have learning and behavioral control difficulties. AIM: The aim of this review is analyse the acute and chronic effect of physical activity (PA) on the cognition and behaviour of children and adolescents with ADHD. METHODS: Studies were identified in five databases (PubMed, SPORTDiscus, ProQuest, Web of Science, and SCOPUS), from January 2000 through to January 2017. A total of 16 interventional studies met the inclusion criteria. RESULTS/CONCLUSIONS: PA practice of 20-30 min (intensity 40-75%) produces a positive acute effect on processing speed, working memory, planning and problem solving in young people with ADHD. However, these effects on behaviour are contradictory and vary depending on age. Chronic PA practice (≥30 min per day, ≥40% intensity, ≥three days per week, ≥five weeks) further improves attention, inhibition, emotional control, behaviour and motor control. The results must be treated with caution, because only 25% of the studies used confounders. IMPLICATION: More research is needed to justify the causes of these effects. It is necessary to establish programs with regard to the duration, intensity, kind of exercise, and time of PA to improve cognition and behaviour in young people with ADHD taking into account potential confounders.

Inhomogeneous Response of Articular Cartilage: A Three-Dimensional Multiphasic Heterogeneous Study.

Articular cartilage exhibits complex mechano-electrochemical behaviour due to its anisotropy, inhomogeneity and material non-linearity. In this work, the thickness and radial dependence of cartilage properties are incorporated into a 3D mechano-electrochemical model to explore the relevance of heterogeneity in the behaviour of the tissue. The model considers four essential phenomena: (i) osmotic pressure, (ii) convective and diffusive processes, (iii) chemical expansion and (iv) three-dimensional through-the-thickness heterogeneity of the tissue. The need to consider heterogeneity in computational simulations of cartilage behaviour and in manufacturing biomaterials mimicking this tissue is discussed. To this end, healthy tibial plateaus from pigs were mechanically and biochemically tested in-vitro. Heterogeneous properties were included in the mechano-electrochemical computational model to simulate tissue swelling. The simulation results demonstrated that swelling of the heterogeneous samples was significantly lower than swelling under homogeneous and isotropic conditions. Furthermore, there was a significant reduction in the flux of water and ions in the former samples. In conclusion, the computational model presented here can be considered as a valuable tool for predicting how the variation of cartilage properties affects its behaviour, opening up possibilities for exploring the requirements of cartilage-mimicking biomaterials for tissue engineering. Besides, the model also allows the establishment of behavioural patterns of swelling and of water and ion fluxes in articular cartilage.

Parameter-dependent behavior of articular cartilage: 3D mechano-electrochemical computational model.

BACKGROUND AND OBJECTIVE: Changes in mechano-electrochemical properties of articular cartilage play an essential role in the majority of cartilage diseases. Despite of this importance, the specific effect of each parameter into tissue behavior remains still obscure. Parametric computational modeling of cartilage can provide some insights into this matter, specifically the study of mechano-electrochemical properties variation and their correlation with tissue swelling, water and ion fluxes. Thus, the aim of this study is to evaluate the influence of the main mechanical and electrochemical parameters on the determination of articular cartilage behavior by a parametric analysis through a 3D finite element model. METHODS: For this purpose, a previous 3D mechano-electrochemical model, developed by the same authors, of articular cartilage behavior has been used. Young's modulus, Poisson coefficient, ion diffusivities and ion activity coefficients variations have been analyzed and quantified through monitoring tissue simulated response. RESULTS: Simulation results show how Young's modulus and Poisson coefficient control tissue behavior rather than electrochemical properties. Meanwhile, ion diffusivity and ion activity coefficients appear to be vital in controlling velocity of incoming and outgoing fluxes. CONCLUSIONS: This parametric study establishes a basic guide when defining the main properties that are essential to be included into computational modeling of articular cartilage providing a helpful tool in tissue simulations.

Altered swelling and ion fluxes in articular cartilage as a biomarker in osteoarthritis and joint immobilization: a computational analysis.

In healthy cartilage, mechano-electrochemical phenomena act together to maintain tissue homeostasis. Osteoarthritis (OA) and degenerative diseases disrupt this biological equilibrium by causing structural deterioration and subsequent dysfunction of the tissue. Swelling and ion flux alteration as well as abnormal ion distribution are proposed as primary indicators of tissue degradation. In this paper, we present an extension of a previous three-dimensional computational model of the cartilage behaviour developed by the authors to simulate the contribution of the main tissue components in its behaviour. The model considers the mechano-electrochemical events as concurrent phenomena in a three-dimensional environment. This model has been extended here to include the effect of repulsion of negative charges attached to proteoglycans. Moreover, we have studied the fluctuation of these charges owning to proteoglycan variations in healthy and pathological articular cartilage. In this sense, standard patterns of healthy and degraded tissue behaviour can be obtained which could be a helpful diagnostic tool. By introducing measured properties of unhealthy cartilage into the computational model, the severity of tissue degeneration can be predicted avoiding complex tissue extraction and subsequent in vitro analysis. In this work, the model has been applied to monitor and analyse cartilage behaviour at different stages of OA and in both short (four, six and eight weeks) and long-term (11 weeks) fully immobilized joints. Simulation results showed marked differences in the corresponding swelling phenomena, in outgoing cation fluxes and in cation distributions. Furthermore, long-term immobilized patients display similar swelling as well as fluxes and distribution of cations to patients in the early stages of OA, thus, preventive treatments are highly recommended to avoid tissue deterioration.

Structural biology response of a collagen hydrogel synthetic extracellular matrix with embedded human fibroblast: computational and experimental analysis.

Adherent cells exert contractile forces which play an important role in the spatial organization of the extracellular matrix (ECM). Due to these forces, the substrate experiments a volume reduction leading to a characteristic shape. ECM contraction is a key process in many biological processes such as embryogenesis, morphogenesis and wound healing. However, little is known about the specific parameters that control this process. With this aim, we present a 3D computational model able to predict the contraction process of a hydrogel matrix due to cell-substrate mechanical interaction. It considers cell-generated forces, substrate deformation, ECM density, cellular migration and proliferation. The model also predicts the cellular spatial distribution and concentration needed to reproduce the contraction process and confirms the minimum value of cellular concentration necessary to initiate the process observed experimentally. The obtained continuum formulation has been implemented in a finite element framework. In parallel, in vitro experiments have been performed to obtain the main model parameters and to validate it. The results demonstrate that cellular forces, migration and proliferation are acting simultaneously to display the ECM contraction.