Lysyl oxidase is a strong determinant of tumor cell colonization in bone

Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase whose primary function is to drive collagen crosslinking and extracellular matrix stiffness. LOX in colorectal cancer synergizes with hypoxia-inducible factor-1 (HIF-1) to promote tumor progression. Here we investigated whether LOX/HIF1 endows colorectal cancer cells with full competence for aggressive colonization in bone. We show that a high LOX expression in primary tumors from patients with colorectal cancer was associated with poor clinical outcome, irrespective of HIF-1. In addition, LOX was expressed by tumor cells in the bone marrow from colorectal cancer patients with bone metastases. In vivo experimental studies show that LOX overexpression in colorectal cancer cells or systemic delivery of the conditioned medium from LOX-overexpressing colorectal cancer cells promoted tumor cell dissemination in the bone marrow and enhanced osteolytic lesion formation, irrespective of HIF-1. Conversely, silencing or pharmacologic inhibition of LOX activity blocked dissemination of colorectal cancer cells in the bone marrow and tumor-driven osteolytic lesion formation. In vitro, tumor-secreted LOX supported the attachment and survival of colorectal cancer cells to and in the bone matrix, and inhibited osteoblast differentiation. LOX overexpression in colorectal cancer cells also induced a robust production of IL6. In turn, both LOX and IL6 were acting in concert to promote RANKL-dependent osteoclast differentiation, thereby creating an imbalance between bone resorption and bone formation. Collectively, our findings show that LOX supports colorectal cancer cell dissemination in the bone marrow and they reveal a novel mechanism through which LOX-driven IL6 production by colorectal cancer cells impairs bone homeostasi

Rheological behaviour of reconstructed skin

International audienceReconstructed skins have been developed to replace skin when the integrity of tissue has been compromised following severe injury, and to provide alternative methods validating the innocuousness and effectiveness of dermatological and cosmetic products. However the functional properties of tissue substitutes have not been well characterised, mainly since mechanical measurement devices have not been designed to test cell culture materials in vitro. From the mechanical standpoint, reconstructed skin is a heterogeneous multi-layer viscoelastic material. To characterise the time-dependent behaviour of reconstructed skin, spherical indentation load-relaxation tests were performed with a specific original device adapted to measure small soft tissue samples. Load-relaxation indentation tests were performed on a standard reconstructed skin model and on sub-components of the reconstructed skin (3D-scaffold alone and dermal equivalent). Generalised Maxwell and Kelvin-Voigt rheological models are proposed for analysing the mechanical behaviour of each biological tissue. The results indicated a modification of the rheological behaviour of the samples tested as a function of their biological structure. The 3D-scaffold was modelled using the one-branch Maxwell model, while the dermis equivalent and the reconstructed skin were modeled using a one-branch and a two-branch Kelvin-Voigt model, respectively. Finally, we demonstrated that skin cells contribute to global mechanical behaviour through an increase of the instantaneous relaxation function, while the 3D-scaffold alone influences the mechanical response of long relaxation times

Disruption of TRPV3 Impairs Heat-Evoked Vasodilation and Thermoregulation: A Critical Role of CGRP.

Sensing environmental temperature is a key factor allowing individuals to maintain thermal homeostasis via thermoregulatory mechanisms, including changes to skin blood flow. Among transient receptor potential channels, transient receptor potential vanilloid 3 (TRPV3) is a heat-activated cation channel highly expressed in keratinocytes. However, the role of TRPV3 in triggering heat-evoked cutaneous vasodilation is unknown. Using a murine in vivo model of local acute environmental heat exposure in the skin, we show that TRPV3 is involved in the local thermoregulatory control of skin blood flow by initiating the release of calcitonin gene-related peptide and nitric oxide in response to local heating of the skin. In addition to their contribution in local heat-evoked vasodilation, TRPV3, calcitonin gene-related peptide, and nitric oxide also contribute to internal body temperature stability during passive whole-body heating. This study provides in vivo demonstration of the role of TRPV3 as a strong modulator of cutaneous vascular thermoregulatory mechanisms

Comparative gene expression profile of mouse carotid body and adrenal medulla under physiological hypoxia

The carotid body (CB) is an arterial chemoreceptor, bearing specialized type I cells that respond to hypoxia by closing specific K(+) channels and releasing neurotransmitters to activate sensory axons. Despite having detailed information on the electrical and neurochemical changes triggered by hypoxia in CB, the knowledge of the molecular components involved in the signalling cascade of the hypoxic response is fragmentary. This study analyses the mouse CB transcriptional changes in response to low P(O(2)) by hybridization to oligonucleotide microarrays. The transcripts were obtained from whole CBs after mice were exposed to either normoxia (21% O(2)), or physiological hypoxia (10% O(2)) for 24 h. The CB transcriptional profiles obtained under these environmental conditions were subtracted from the profile of control non-chemoreceptor adrenal medulla extracted from the same animals. Given the common developmental origin of these two organs, they share many properties but differ specifically in their response to O(2). Our analysis revealed 751 probe sets regulated specifically in CB under hypoxia (388 up-regulated and 363 down-regulated). These results were corroborated by assessing the transcriptional changes of selected genes under physiological hypoxia with quantitative RT-PCR. Our microarray experiments revealed a number of CB-expressed genes (e.g. TH, ferritin and triosephosphate isomerase) that were known to change their expression under hypoxia. However, we also found novel genes that consistently changed their expression under physiological hypoxia. Among them, a group of ion channels show specific regulation in CB: the potassium channels Kir6.1 and Kcnn4 are up-regulated, while the modulatory subunit Kcnab1 is down-regulated by low P(O(2)) levels