Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling

Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model. Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells

Radiation-induced collateral damage : impact on metastasis

Public defense: 2016-03-21D

FHL2: A scaffold protein of carcinogenesis, tumour-stroma interactions and treatment response

Four-and-a-half LIM-domain protein 2 (FHL2) is a multifunctional scaffolding protein regulating signalling cascades and gene transcription. It shuttles between focal adhesions and the nucleus where it signals through direct interaction with a number of proteins including β-catenin. The multiplicity of molecular pathways affected by FHL2 suggests an important role in several physiological and pathological events. The function of FHL2 in cancer is particularly intriguing, since it may act as an oncoprotein or as a tumour suppressor in a tissue-dependent fashion. In this review we present the current knowledge on the role of FHL2 in carcinogenesis, with emphasis on the digestive tract. We discuss the overexpression of FHL2 in colorectal, gastric and pancreatic cancer, the downregulation in hepatocellular carcinoma and the role of FHL2 in epithelial-mesenchymal transition. We briefly look at the potential role of FHL2 in the tumoural microenvironment and discuss how FHL2 expression and function might influence cancer treatment. Before implementation of FHL2 as a biomarker by pathologists, antibody validation should, however, be carried out

FHL2 : a scaffold protein of carcinogenesis, tumour-stroma interactions and treatment response

Four-and-a-half LIM-domain protein 2 (FHL2) is a multifunctional scaffolding protein regulating signalling cascades and gene transcription. It shuttles between focal adhesions and the nucleus where it signals through direct interaction with a number of proteins including beta-catenin. The multiplicity of molecular pathways affected by FHL2 suggests an important role in several physiological and pathological events. The function of FHL2 in cancer is particularly intriguing, since it may act as an oncoprotein or as a tumour suppressor in a tissue-dependent fashion. In this review we present the current knowledge on the role of FHL2 in carcinogenesis, with emphasis on the digestive tract. We discuss the overexpression of FHL2 in colorectal, gastric and pancreatic cancer, the downregulation in hepatocellular carcinoma and the role of FHL2 in epithelial-mesenchymal transition. We briefly look at the potential role of FHL2 in the tumoural microenvironment and discuss how FHL2 expression and function might influence cancer treatment. Before implementation of FHL2 as a biomarker by pathologists, antibody validation should, however, be carried out

The relation between spasticity and muscle behavior during the swing phase of gait in children with cerebral palsy

There is much debate about how spasticity contributes to the movement abnormalities seen in children with spastic cerebral palsy (CP). This study explored the relation between stretch reflex characteristics in passive muscles and markers of spasticity during gait. Twenty-four children with CP underwent 3D gait analysis at three walking velocity conditions (self-selected, faster and fastest). The gastrocnemius (GAS) and medial hamstrings (MEHs) were assessed at rest using an instrumented spasticity assessment that determined the stretch-reflex threshold, expressed in terms of muscle lengthening velocity. Muscle activation was quantified with root mean square electromyography (RMS-EMG) during passive muscle stretch and during the muscle lengthening periods in the swing phase of gait. Parameters from passive stretch were compared to those from gait analysis. In about half the children, GAS peak muscle lengthening velocity during the swing phase of gait did not exceed its stretch reflex threshold. In contrast, in the MEHs the threshold was always exceeded. In the GAS, stretch reflex thresholds were positively correlated to peak muscle lengthening velocity during the swing phase of gait at the faster (r=0.46) and fastest (r=0.54) walking conditions. In the MEHs, a similar relation was found, but only at the faster walking condition (r=0.43). RMS-EMG during passive stretch showed moderate correlations to RMS-EMG during the swing phase of gait in the GAS (r=0.46-0.56) and good correlations in the MEHs (r=0.69-0.77) at all walking conditions. RMS-EMG during passive stretch showed no correlations to peak muscle lengthening velocity during gait. We conclude that a reduced stretch reflex threshold in the GAS and MEHs constrains peak muscle lengthening velocity during gait in children with CP. With increasing walking velocity, this constraint is more marked in the GAS, but not in the MEHs. Hyper-activation of stretch reflexes during passive stretch is related to muscle activation during the swing phase of gait, but has a limited contribution to reduced muscle lengthening velocity during swing. Larger studies are required to confirm these results, and to investigate the contribution of other impairments such as passive stiffness and weakness to reduced muscle lengthening velocity during the swing phase of gait.publisher: Elsevier articletitle: The relation between spasticity and muscle behavior during the swing phase of gait in children with cerebral palsy journaltitle: Research in Developmental Disabilities articlelink: http://dx.doi.org/10.1016/j.ridd.2014.07.053 content_type: article copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.status: publishe

The relation between spasticity and muscle behavior during the swing phase of gait in children with cerebral palsy

There is much debate about how spasticity contributes to the movement abnormalities seen in children with spastic cerebral palsy (CP). This study explored the relation between stretch reflex characteristics in passive muscles and markers of spasticity during gait. Twenty-four children with CP underwent 3D gait analysis at three walking velocity conditions (self-selected, faster and fastest). The gastrocnemius (GAS) and medial hamstrings (MEHs) were assessed at rest using an instrumented spasticity assessment that determined the stretch-reflex threshold, expressed in terms of muscle lengthening velocity. Muscle activation was quantified with root mean square electromyography (RMS-EMG) during passive muscle stretch and during the muscle lengthening periods in the swing phase of gait. Parameters from passive stretch were compared to those from gait analysis. In about half the children, GAS peak muscle lengthening velocity during the swing phase of gait did not exceed its stretch reflex threshold. In contrast, in the MEHs the threshold was always exceeded. In the GAS, stretch reflex thresholds were positively correlated to peak muscle lengthening velocity during the swing phase of gait at the faster (r=. 0.46) and fastest (r=. 0.54) walking conditions. In the MEHs, a similar relation was found, but only at the faster walking condition (r=. 0.43). RMS-EMG during passive stretch showed moderate correlations to RMS-EMG during the swing phase of gait in the GAS (r=. 0.46-0.56) and good correlations in the MEHs (r=. 0.69-0.77) at all walking conditions. RMS-EMG during passive stretch showed no correlations to peak muscle lengthening velocity during gait. We conclude that a reduced stretch reflex threshold in the GAS and MEHs constrains peak muscle lengthening velocity during gait in children with CP. With increasing walking velocity, this constraint is more marked in the GAS, but not in the MEHs. Hyper-activation of stretch reflexes during passive stretch is related to muscle activation during the swing phase of gait, but has a limited contribution to reduced muscle lengthening velocity during swing. Larger studies are required to confirm these results, and to investigate the contribution of other impairments such as passive stiffness and weakness to reduced muscle lengthening velocity during the swing phase of gait

Spasticity and Its Contribution to Hypertonia in Cerebral Palsy

Spasticity is considered an important neural contributor to muscle hypertonia in children with cerebral palsy (CP). It is most often treated with antispasticity medication, such as Botulinum Toxin-A. However, treatment response is highly variable. Part of this variability may be due to the inability of clinical tests to differentiate between the neural (e.g., spasticity) and nonneural (e.g., soft tissue properties) contributions to hypertonia, leading to the terms "spasticity" and "hypertonia" often being used interchangeably. Recent advancements in instrumented spasticity assessments offer objective measurement methods for distinction and quantification of hypertonia components. These methods can be applied in clinical settings and their results used to fine-tune and improve treatment. We reviewed current advancements and new insights with respect to quantifying spasticity and its contribution to muscle hypertonia in children with CP. First, we revisit what is known about spasticity in children with CP, including the various definitions and its pathophysiology. Second, we summarize the state of the art on instrumented spasticity assessment in CP and review the parameters developed to quantify the neural and nonneural components of hypertonia. Lastly, the impact these quantitative parameters have on clinical decision-making is considered and recommendations for future clinical and research investigations are discussed.status: publishe