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Purpose: Osteosarcoma, the most common bone tumor, lacks prognostic markers that could distinguish patients before therapy and drive treatment choices. We assessed the prognostic value of CCN1, CCN2, and CCN3 genes, involved in fundamental biological processes.Experimental Design: Expression of CCN1, CCN2, and CCN3 was measured by quantitative PCR in 45 newly diagnosed osteosarcomas. Cancer-specific survival was estimated using the Kaplan-Meier method. Associations with osteoblastic differentiation and/or drug response genes were assessed in tumor cells using Spearman correlation and Fisher's exact tests.Results:CCN1 and CCN2 expression was associated with genes involved in commitment of mesenchymal stem cells toward osteoblasts and in early phases of osteoblastic differentiation (RUNX family genes; cadherin 4, 11, and 13; jun and fos; collagen I and SPARC). Although CCN3 is barely expressed in normal proliferating osteoblasts and mesenchymal stem cells, its expression was generally high in osteosarcoma and its level of expression did not correlate with any specific osteoblastic differentiation genes. High expression of CCN3 significantly correlated with worse prognosis in osteosarcoma. This may be only partly explained by the association with the expression of multidrug resistance–related protein 1 and 4, two ATP-binding cassette transporters that also acted as predictors of worse outcome in our study.Conclusions: Our study showed temporal and coordinated expression of CCN1, CCN2, and CCN3 genes during osteoblastic differentiation and highlighted significant differences between human normal and osteosarcoma cell differentiation in vitro. CCN1 and CCN2 expression shows no prognostic relevance in osteosarcoma. In contrast, assessment for CCN3 expression levels at diagnosis may represent a useful molecular tool to early identification of patients with different prognosis.

Supplementary Figure 1 from CCN3/Nephroblastoma Overexpressed Matricellular Protein Regulates Integrin Expression, Adhesion, and Dissemination in Melanoma

CCN3/nephroblastoma overexpressed belongs to the CCN family of genes that encode secreted proteins associated with the extracellular matrix (ECM) and exert regulatory effects at the cellular level. Overexpression of CCN3 was shown in metastatic melanoma cells compared with cells of the primary tumor from the same patient. Analysis of short-term cultures from 50 primary and metastatic melanomas revealed a heterogeneous expression pattern of both the 46-kDa full-length cytoplasmic/secreted protein and the 32-kDa nuclear-truncated form. The different protein expression patterns were not associated with gene alterations or polymorphisms. Like the metastatic cells expressing high levels of the 46-kDa CCN3, cells transfected to overexpress CCN3 showed increased adhesion to ECM proteins, whereas inhibition of CCN3 expression by small interfering RNA decreased adhesion to laminin and vitronectin. CCN3 overexpression induced increased expression of laminin and vitronectin integrin receptors α7β1 and αvβ5 by increasing their mRNA production. Moreover, CCN3 secreted by melanoma cells acted as an adhesion matrix protein for melanoma cells themselves. Analysis of CCN3 protein expression with respect to melanoma progression detected the protein in all visceral metastases tested and in most nodal metastases from relapsing patients but in only a few nodal metastases from nonrelapsing patients and cutaneous metastases. Consistently, xenotransplantation in immunodeficient mice showed a higher metastatic potential of melanoma cells overexpressing CCN3. Together, these data indicate a role for CCN3 in melanoma cell interaction with the ECM by regulating integrin expression, resulting in altered cell adhesion and leading melanoma progression to aggressive disease. [Cancer Res 2008;68(3):715–23]

Supplementary Methods, Figure 1 Legend , Tables 1-2 from CCN3/Nephroblastoma Overexpressed Matricellular Protein Regulates Integrin Expression, Adhesion, and Dissemination in Melanoma

A little over a year ago, on January 25, 2021, the new Editor-in-Chief (EiC) of JCCS stated in his Editorial: “ICCNS and JCCS were the brainchildren of Bernard Perbal, and without his energy and drive, neither would exist, to the detriment of us who are driven to solve difficult problems in science, and not picking low-hanging fruit. All one has to do is examine all the editorials written in JCCS (and CCS!) to see evidence of this. It will be tough to fill those shoes.“ I disagree with the assertion in the Editorial published on March 29, 2022 that G. Martin contributed “to the initial growth of the International CCN Society, and, ultimately, to the establishment of this journal.” My opinion is based on the evidence that the International CCN Society (ICCNS) and its official organ journal, the Journal of Cell Communication and Signaling (JCCS), were created by myself. Over a span of 21 years until the present, and in spite of his contribution to the early history of CTGF, we never heard from G. Martin being involved or interested in any aspect of the ICCNS and its biannual meetings, nor in any aspect in the growth of JCCS. In order to further clarify the confusion stemming from the Editorial in question and to give credit where it is due, I provide below detailed evidence that undoubtedly ascribes the true inception of both ICCNS and JCCS, and merit to the efforts of all those who trusted and supported us during the initial difficult creative moments. I am of the opinion that the Editorial, and the implications that it carries do not justice to the efforts of those who were really involved in the creation of both the ICCNS and JCCS. In the name of respectful scientific integrity, I will provide the evidence that correctly attributes the inception of ICCNS and JCCS.

Cellular communication network factor (CCN) 3, which is one of the founding members of the CCN family, displays diverse functions. However, this protein generally represses the proliferation of a variety of cells. Along with skeletal development, CCN3 is produced in cartilaginous anlagen, growth plate cartilage and epiphysial cartilage. Interestingly, CCN3 is drastically induced in the growth plates of mice lacking CCN2, which promotes endochondral ossification. Notably, chondrocytes in these mutant mice with elevated CCN3 production also suffer from impaired glycolysis and energy metabolism, suggesting a critical role of CCN3 in cartilage metabolism. Recently, CCN3 was found to be strongly induced by impaired glycolysis, and in our study, we located an enhancer that mediated CCN3 regulation via starvation. Subsequent investigations specified regulatory factor binding to the X-box 1 (RFX1) as a transcription factor mediating this CCN3 regulation. Impaired glycolysis is a serious problem, resulting in an energy shortage in cartilage without vasculature. CCN3 produced under such starved conditions restricts energy consumption by repressing cell proliferation, leading chondrocytes to quiescence and survival. This CCN3 regulatory system is indicated to play an important role in articular cartilage maintenance, as well as in skeletal development. Furthermore, CCN3 continues to regulate cartilage metabolism even during the aging process, probably utilizing this regulatory system. Altogether, CCN3 seems to prevent "overwork" by chondrocytes to ensure their sustainable life in cartilage by sensing energy metabolism. Similar roles are suspected to exist in relation to systemic metabolism, since CCN3 is found in the bloodstream.

According to Chinese astrology, the Tiger is considered as the king of all animals. The Year of the Tiger 2022 was meant to symbolize determinism, vitality, strength, spontaneity and novelty, with the water element making it wiser and thoughtful. Often associated with the defeat of evil, a Water Tiger year occurs only every 60 years. The 2022 version was indeed a year of resilience, even in the time of conflict and the struggles that we have faced both in personal and professional realms. It was a good time to reflect in order to overcome all challenges and difficulties. The revamping of both the International CCN society (ICCNS) and the Journal of Cell Communication and Signaling (JCCS) that I had previously initiated and officially announced in 2019, are on track to becoming a successful reality and will be pursued over the coming years, thanks to the strong support of our colleagues, members of the JCCS Editorial board and representatives of other scientific societies who support our efforts to broaden the scope of the ICCNS and its communication organ. I will schematically draw below the guidelines that we intend to follow in the near future.

Since the authors first reviewed this subject in 2016 significant progress has been documented in the CCN field with advances made in the understanding of how members of the CCN family of proteins, CCN1-6, contribute to the pathogenesis and progression, positive and negative, of a larger variety of cancers. As termed matricellular proteins, and more recently the connective communication network, it has become clearer that members of the CCN family interact complexly with other proteins in the extracellular microenvironment, membrane signaling proteins, and can also operate intracellularly at the transcriptional level. In this review we expand on this earlier information providing new detailed information and insights that appropriate a much greater involvement and importance of their role in multiple aspects of cancer. Despite all the new information many more questions have been raised and intriguing results generated that warrant greater investigation. In order to permit the reader to smoothly integrate the new information we discuss all relevant CCN members in the context of cancer subtypes. We have harmonized the nomenclature with CCN numbering for easier comparisons. Finally, we summarize what new has been learned and provide a perspective on how our knowledge about CCN1-6 is being used to drive new initiatives on cancer therapeutics.

In this editorial I briefly review the new JCCS scientific directions that have emerged from the complicated situations created by the pandemics of COVID- 19, and by the internal audit of both Journal of Cell Communication and Signaling and International CCN Society, that were initiated since my proposal at the 2019 International Workshop on the CCN family of genes.I also welcome the distinguished members of our renewed JCCS Editorial and congratulate all those who have in many different ways participated to the consolidation of the 2021 JCCS Impact Factor attaining 5.908.

Systems that have yet to stand the test of time carry imperfections that need to be skillfully addressed with the least amount of authoritarianism as possible. The communication and transmission of knowledge that we hold dear are essential pillars to social progress. As such, it is necessary to analyze with the greatest scientific objectivity the applications arising from the deep revolution rooted in the total sequencing of the human genome which affects all aspects of our societies. This extraordinary advance in human knowledge and the resulting technological achievements should not lend themselves to the fears or fantasies often fueled by those who criticize all scientific progress calling into question the most established dogmas. Certain supposedly scholarly analyses of the health situation with which we are currently confronted worldwide are a perfect illustration of this unfortunate trend. It is undeniable that the progress of molecular genetics has opened up a wide range of applications in many fields, affecting the well-being of humans, their mental and physical health. The apparent universal and individual interest for the most advanced genetic profile analyzing technologies is a testimony to this strong common desire to better understand one’s genetic heritage and to control their usage. Despite this movement, little attention is given to the recent advances in genetics applied to essential aspects of the social life of individuals through their inter-personal interactions. It is particularly distressing that the contributions of molecular biology and genetics to the daily well-being of individuals have not yet allowed open-access non-medical genetic testing to gain the recognition it deserves and are still viewed as recreational applications. Through an analysis of the cross influences that genetic biotechnologies have had since the beginning of the century in the fields of nutrition and cosmetics, we have tried to project ourselves into the near future which should witness major behavioral and social upheavals.

The recent increase of the Journal of Cell Signaling and Communication’ 2020 Impact Factor to 5.782, and its growing audience in the scientific community, provides an opportunity to step back and look at different aspects of this indicator’s value. The take home message is that the top-ten major contributions to the 2020 ranking originated from North America and Europe followed by India with a high percentage of CCN-related publications and an excellent proportion of Editorial Board members’ contributions to the Top10 best citations for the 2018–2019 period.

Cellular communication network factor (CCN) 3 is one of the classical members of the CCN family, which are characterized by common molecular structures and multiple functionalities. Although this protein was discovered as a gene product overexpressed in a truncated form in nephroblastoma, recent studies have revealed its physiological roles in the development and homeostasis of mammalian species, in addition to its pathological association with a number of diseases. Cartilage is a tissue that creates most of the bony parts and cartilaginous tissues that constitute the human skeleton, in which CCN3 is also differentially produced to exert its molecular missions therein. In this review article, after the summary of the molecular structure and function of CCN3, recent findings on the regulation of ccn3 expression and the roles of CCN3 in endochondral ossification, cartilage development, maintenance and disorders are introduced with an emphasis on the metabolic regulation and function of this matricellular multifunctional molecule.

Background Multiple sclerosis (MS) is an immune-mediated disease that damages myelin in the central nervous system (CNS). We investigated the profile of CCN3, a known regulator of immune function and a potential mediator of myelin regeneration, in multiple sclerosis in the context of disease state and disease-modifying treatment. Methods CCN3 expression was analysed in plasma, immune cells, CSF and brain tissue of MS patient groups and control subjects by ELISA, western blot, qPCR, histology and in situ hybridization. Results Plasma CCN3 levels were comparable between collective MS cohorts and controls but were significantly higher in progressive versus relapsing-remitting MS and between patients on interferon-β versus natalizumab. Higher body mass index was associated with higher CCN3 levels in controls as reported previously, but this correlation was absent in MS patients. A significant positive correlation was found between CCN3 levels in matched plasma and CSF of MS patients which was absent in a comparator group of idiopathic intracranial hypertension patients. PBMCs and CD4+ T cells significantly upregulated CCN3 mRNA in MS patients versus controls. In the CNS, CCN3 was detected in neurons, astrocytes and blood vessels. Although overall levels of area immunoreactivity were comparable between non-affected, demyelinated and remyelinated tissue, the profile of expression varied dramatically. Conclusions This investigation provides the first comprehensive profile of CCN3 expression in MS and provides rationale to determine if CCN3 contributes to neuroimmunological functions in the CNS.

Significance Remyelination is a natural regenerative process driven by oligodendrocytes that occurs following myelin damage. Understanding this process holds therapeutic value for demyelinating diseases such as multiple sclerosis, in which remyelination can fail. CCN3 is a matricellular protein previously reported to enhance oligodendrocyte progenitor differentiation and myelination in vitro and ex vivo. Here, we show that despite extensive and dynamic expression in the murine CNS in homeostasis and following toxin-induced myelin damage, CCN3 is not required for myelination or remyelination in vivo. Yet, the anatomically distinct expression pattern suggests unidentified roles of CCN3 in a range of neurological processes. This investigation provides a framework for future investigations of the expression and role of CCN proteins in the CNS., CCN3 is a matricellular protein that promotes oligodendrocyte progenitor cell differentiation and myelination in vitro and ex vivo. CCN3 is therefore a candidate of interest in central nervous system (CNS) myelination and remyelination, and we sought to investigate the expression and role of CCN3 during these processes. We found CCN3 to be expressed predominantly by neurons in distinct areas of the CNS, primarily the cerebral cortex, hippocampus, amygdala, suprachiasmatic nuclei, anterior olfactory nuclei, and spinal cord gray matter. CCN3 was transiently up-regulated following demyelination in the brain of cuprizone-fed mice and spinal cord lesions of mice injected with lysolecithin. However, CCN3−/− mice did not exhibit significantly different numbers of oligodendroglia or differentiated oligodendrocytes in the healthy or remyelinating CNS, compared to WT controls. These results suggest that despite robust and dynamic expression in the CNS, CCN3 is not required for efficient myelination or remyelination in the murine CNS in vivo.

The wide array of biological properties attributed to the CCN family of proteins (Perbal in Lancet 363(9402):62–64, 2004) led me to reconsider the possible relationship and roles that these proteins may play as a team, instead of acting on their own as individual regulators in various signaling pathways. The dynamic model which I present in this review stems from the contribution of the biological properties that we established for CCN3, one of the three founding members of the CCN family, which was identified by our group as the first CCN protein showing growth inhibitory properties (1992), expressed mainly in quiescent cells (1996), and showing anti-tumor activities in several cellular models both ex vivo and in vivo. At the present time CCN3 is the only member of the family that has been reported to negatively act on the progression of the cell cycle. The unique dual localisation of CCN3 in the nucleus and outside cells, either at the membrane or in the extracellular matrix, that I first established in 1999, and that now appears to be shared by several other CCN proteins, is a unique essential feature which can no longer be ignored. Based on the structural and functional properties of CCN3, shared by most of the CCN family members, I propose an « all in one » concept in which CCN proteins are team members with specific functions that are aimed at the same goal. This model accounts both for the functional specificity of the various CCN proteins, their sequential and opposite or complementary effects in various biological context, and for the biological consequences of their physical interaction and biological cross-regulation.

Recent studies implicate the Cyr61, CTGF, Nov (CCN) matricellular signaling protein family as emerging players in vascular biology, with NOV (alias CCN3) as an important regulator of vascular homeostasis. Herein, we examined the role of CCN3 in the pathogenesis of atherosclerosis. In response to a 15-week high-fat diet feeding, CCN3-deficient mice on the atherosclerosis-prone Apoe−/− background developed increased aortic lipid-rich plaques compared to control Apoe−/− mice, a result that was observed in the absence of alterations in plasma lipid content. To address the cellular contributor(s) responsible for the atherosclerotic phenotype, we performed bone marrow transplantation experiments. Transplantation of Apoe; Ccn3 double-knockout bone marrow into Apoe−/− mice resulted in an increase of atherosclerotic plaque burden, whereas transplantation of Apoe−/− marrow to Apoe; Ccn3 double-knockout mice caused a reduction of atherosclerosis. These results indicate that CCN3 deficiency, specifically in the bone marrow, plays a major role in the development of atherosclerosis. Mechanistically, cell-based studies in isolated peritoneal macrophages demonstrated that CCN3 deficiency leads to an increase of lipid uptake and foam cell formation, an effect potentially attributed to the increased expression of scavenger receptors CD36 and SRA1, key factors involved in lipoprotein uptake. These results suggest that bone marrow–derived CCN3 is an essential regulator of atherosclerosis and point to a novel role of CCN3 in modulating lipid accumulation within macrophages.

The lethal phenotype of castration-resistant prostate cancer (CRPC) is generally caused by augmented signaling from the androgen receptor (AR). Here, we report that the AR-repressed gene CCN3/NOV inhibits AR signaling and acts in a negative feedback loop to block AR function. Mechanistically, a cytoplasmic form of CCN3 interacted with the AR N-terminal domain to sequester AR in the cytoplasm of prostate cancer cells, thereby reducing AR transcriptional activity and inhibiting cell growth. However, constitutive repression of CCN3 by the Polycomb group protein EZH2 disrupted this negative feedback loop in both CRPC and enzalutamide-resistant prostate cancer cells. Notably, restoring CCN3 was sufficient to effectively reduce CPRC cell proliferation in vitro and to abolish xenograft tumor growth in vivo. Taken together, our findings establish CCN3 as a pivotal regulator of AR signaling and prostate cancer progression and suggest a functional intersection between Polycomb and AR signaling in CRPC. Cancer Res; 77(2); 412–22. ©2016 AACR.

The CCN family of proteins consisting of CCN1 (Cyr61), CCN2 (CTGF), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2) and CCN6 (WISP-3) are considered matricellular proteins operating essentially in the extracellular microenvironment between cells. Evidence has also been gradually building since their first discovery of additional intracellular roles although the major activity is triggered at the cell membrane. The proteins consist of 4 motifs, a signal peptide (for secretion} followed consecutively by the IGFBP, VWC, TSP1 and CT (C-terminal cysteine knot domain) motifs, which signify their potential binding partners and functional connections to a variety of key regulators of physiological processes. With respect to cancer it is now clear that, whereas certain members can facilitate tumor behavior and progression, others can competitively counter the process. It is therefore clear that the net outcome of biological interactions in the matrix and what gets signaled or inhibited can be a function of the interplay of these CCN 1-6 proteins. Because the CCN proteins further interact with other key proteins, like growth factors in the matrix, the balance is not only important but can vary dynamically with the physiological states of tumor cells and the surrounding normal cells. The tumor niche with its many cell players has surfaced as a critical determinant of tumor behavior, invasiveness, and metastasis. It is in this context that CCN proteins should be investigated with the potential of being recognized and validated for future therapeutic approaches.

An examination of the confusion generated around the use of different acronyms for CCN proteins has been performed by the editors of the HUGO Gene Nomenclature Committee upon the request of the International CCN Society Scientific Committee. After careful consideration of the various arguments, and after polling the community of researchers who have published in the field over the past ten years, the HGNC have decided to adopt and approve the CCN nomenclature for all 6 genes. Effective October 2018, the genes referred to as CYR61, CTGF, NOV and WISP1–3 will be respectively designated by the gene symbols CCN1–6 with corresponding gene names « cellular communication Q2 network factor 1–6 ». We believe that this decision will be a step towards better communication between researchers working in the field, and will set the stage for fruitful collaborative projects. Accordingly, the Journal of Cell Communication and Signaling, the official journal of the International CCN Society, available both in print and online, constitutes a unique window into the CCN field. This official nomenclature will benefit the international scientific community that is supported by the established and renowned professionalism of the Springer-Nature publishing group.

Metastatic melanoma is highly fatal. Within the tumor microenvironment, the role of cancer-associated fibroblasts (CAFs) in melanoma metastasis and progression is relatively understudied. The matricellular protein CCN2 (formerly termed connective tissue growth factor, CTGF) is overexpressed, in a fashion independent of BRAF mutational status, by CAFs in melanoma. Herein, we find, in human melanoma patients, that CCN2 expression negatively correlates with survival and positively correlates with expression of neovascularization markers. To assess the role of CAFs in melanoma progression, we used C57BL/6 mice expressing a tamoxifen-dependent cre recombinase expressed under the control of a fibroblast-specific promoter/enhancer (COL1A2) to delete CCN2 postnatally in fibroblasts. Mice deleted or not for CCN2 in fibroblasts were injected subcutaneously with B16-F10 melanoma cells. Loss of CCN2 in CAFs resulted in reduced CAF activation, as detected by staining with anti-α-smooth muscle actin antibodies, and reduced tumor-induced neovascularization, as detected by micro-computed tomography (micro-CT) and staining with anti-CD31 antibodies. CCN2-deficient B16(F10) cells were defective in a tubule formation/vasculogenic mimicry assay in vitro. Mice deleted for CCN2 in CAFs also showed impaired vasculogenic mimicry of subcutaneously-injected B16-F10 cells in vivo. Our results provide new insights into the cross-talk among different cell types in the tumor microenvironment and suggest CAFs play a heretofore unappreciated role by being essential for tumor neovascularization via the production of CCN2. Our data are consistent with the hypothesis that activated CAFs are essential for melanoma metastasis and that, due to its role in this process, CCN2 is a therapeutic target for melanoma.

As part of the Journal of Cell communication and Signaling publishing staff, we are very much attached to the freedom of expression given to our authors. This has been exemplified in our willingness to stimulate commentaries and open debates through the Bits and Bytes series published in JCCS. Without willing to take part in the debate regarding the nature of the drawings published in Charlie Hebdo, we recognize the worldwide response to the recent murdering of journalists as strong support of freedom of the press , however, we also felt that attempts to silence other forms of expression, which are numerous these days, should be reminded and fought against. In this editorial we pay homage to the victims of recent tragic events in Paris and to all who fight every day for freedom of expression.

Previous studies have indicated that the expression of CCN3, a member of the CCN family of proteins, was tightly regulated during central nervous development and was associated with acquisition of cognitive functions in rats (Perbal, Mol Pathol 54(2):57–79, 2001; Su et al. Sheng Li Xue Bao 52(4):290–294, 2000) therefore suggesting that CCN3 might be involved in higher levels of physiological communication in the brain. In spite of the considerable amount of progress made into the understanding of neuronal organization and communication, reducing the knowledge gap between brain cellular biology and behavioral studies remains a huge challenge. Mind-to-mind communication has been the subject of numerous science fiction writings, intense research and emotional debates for many years. Scientists have tried for a long time to achieve transmission of messages between living subjects via non intrusive protocols. Thanks to the great progress made in imagery and neurosciences, another dimension of neuronal function in communication has now been documented. Two recent experimental demonstrations of direct brain to brain communication without physical contact (Grau et al. (2014) Conscious brain-to-brain communication in humans using non-invasive technologies. PLoS One. Aug 19;9(8)- - Rao et al. (2014) A direct brain-to-brain interface in humans. PLoS One. Nov 5;9(11)) pave the road to more sophisticated applications that could profoundly affect communications of humans with other humans, animals and machines. Although the wide use of such applications might seem a long way off, they raise quite a number of ethical, legal and societal issues.

On behalf of the Journal of Cell Communication and Signaling Editorial board it is my great pleasure to present through this message of peace and love our warmest wishes of health, happiness and professional success. We sincerely hope that 2017 will be a peaceful year worldwide and that solutions will be brought to resolve the great tensions that crystalized last year into terrible acts of violence which reflected the inability of the political powers to bring satisfactory solutions to human dispair and fear. The year 2017 will be the time for celebration of the 10th JCCS anniversary and 9th International Workshop on the CCN family of Genes. Both events should allow us to meet in a productive interactive way. I have had the opportunity to express several times in these columns my deep belief in the power of communication at all levels of human biological and social interactions. Indeed, « Communication is the key » at large.

In this report, chairs of the 7th International Workshop on the CCN family of Genes, review the progress made in understanding the biological functions of CCN proteins (CCN1, CCN2, CCN3, CCN4, CCN5 and CCN6) with a particular focus on their implications in various pathological conditions, including cancer, fibrosis, diabetes, and cardiovascular diseases.

The Nuts and Bolts section of our Journal (mirrored on the ICCNS society web site), is meant to provide a very practical way to share useful information, that goes beyond the scope of cell signaling and basic CCN protein biology. Considering the number of requests we have had for information related to protection of Intellectual Property (IP), I am pleased to initiate what will be a series of articles that will focus on various IP topics. The inaugural topic is the protection of computer programs. Some colleagues may wonder how and why the patentability of computer programs is a topic of interest for scientists working on CCN proteins . . . As a matter of fact, to assist us in analyzing the potential involvement of CCN3 in human genetic diseases, we considered developing a computer program designed to analyze large amounts of data. Sharing the concepts and the computer program raised concerns regarding IP and protection of the software that we would handle. We believe that many colleagues have encountered similar problems. This article provides a short focus on computer program patentability. It is aimed to provide basic legal information, and to help our readers in understanding the process. It is not intended to replace IP counselors or technology transfer departments. Future articles will address other practical aspects of IP protection.

The original version of this article unfortunately contained a mistake. In the Abstract section, a production query number (Q2) was inadvertently inserted within the new official gene names of the CCN proteins.

The human gut microflora has drawn a lot of attention as a potent therapeutic tool for many decades. More recently, efforts have been developed to devise efficient ways of complementing or replacing deficient intestinal microflora associated with intestinal diseases that are resistant to conventional medical treatments. Aside from the medical and industrial applications that emerged from the use of gut microbiota, the complex constitution of this ecosystem raises fascinating questions regarding host-cell communication and host response mechanisms to the ever changing environment. This brief comment also points to questions raised by some unexpected applications that have recently emerged from this field.

With this special issue we celebrate 25 years of publishing in the field of CCN protein biology. Since the very first publications reporting the existence of these proteins, strong relationships have been established between the disregulation in the expression of CCN proteins and the development of cancer.

The year 2016 will see significant improvements for the Journal of Cell Communication and Signaling with the earning of an official Impact Factor and the merger of Springer Science + Business Media and part of Macmillan Sciences and Education. It will also be an important year for the International CCN Society (ICCNS) with the nomination of a new Scientific Board and reinforcement of interactions with other major scientific societies interested in various aspects of Cell Signaling. Starting this year the ICCNS will become an official provider of CCN3 knock out mice to ICCNS members. This first step in opening up access to certified reagents as a service for our CCN scientific community is part of our intention and efforts to attain the highest degree of assistance and enabler of scientific cooperation and communication in Science Communication.

In a recent manuscript, Goff and collaborators (Metzger et al. 2016) reported data arguing for the spread of contagious cancer cells among different species of shellfish. Although horizontal transmission of cancer cells has been observed in a few cases in higher organisms, it appears to be rather frequent among molluscs. Recent evidence supports the concept of inter-species horizontal infectious transmission of cancer cells both in molluscs but also in mammals, including humans.

The CCN family of proteins is composed of six members, which are now well recognized as major players in fundamental biological processes. The first three CCN proteins discovered were designated CYR61, CTGF, and NOV because of the context in which they were identified. Both CYR61 and CTGF were discovered in normal cells, whereas NOV was identified in tumors. Soon after their discovery, it was established that they shared important and unique structural features and distinct biological properties. Based on these structural considerations, the three proteins were proposed to belong to a family that was designated CCN by P. Bork. Hence the CCN1, CCN2 and CCN3 acronyms. The family grew to six members a few years later with the description of three proteins WISP-1, WISP-2 and WISP-3 (CCN4, CCN5 and CCN6), that shared the same tetramodular and conserved structural features. With the functions of the CCN proteins being uncovered, this raised a nomenclature problem. A scientific committee convened in Saint Malo (France) proposed to apply the CCN nomenclature to the six members of the family. Although the unified nomenclature was proposed in order to avoid serious misconceptions and lack of precision associated with the use of the old acronyms, the acceptance of the new acronyms has taken time. In order to evaluate how the use of disparate nomenclatures have had an impact on the CCN protein field, we conducted a survey of the articles that have been published in this area since the discovery of the first CCN proteins and inception of the field. We report in this manuscript the confusion and serious deleterious scientific consequences that have stemmed from a disorganized usage of several unrelated acronyms. The conclusions that we have reached call for a unification that needs to overcome personal habits and feelings. Instead of allowing the CCN field to fully crystalize and gain the recognition that it deserves the usage of many different acronyms represents a danger that everyone must fight against in order to avoid its deliquescence. We hope that the considerations discussed in the present article will encourage all authors working in the CCN field to work jointly and succeed in building a strong and coherent CCN scientific community that will benefit all of us.

Abdominal aortic aneurysm (AAA) is a major cause of morbidity and mortality; however, the mechanisms that are involved in disease initiation and progression are incompletely understood. Extracellular matrix proteins play an integral role in modulating vascular homeostasis in health and disease. Here, we determined that the expression of the matricellular protein CCN3 is strongly reduced in rodent AAA models, including angiotensin II-induced AAA and elastase perfusion-stimulated AAA. CCN3 levels were also reduced in human AAA biopsies compared with those in controls. In murine models of induced AAA, germline deletion of Ccn3 resulted in severe phenotypes characterized by elastin fragmentation, vessel dilation, vascular inflammation, dissection, heightened ROS generation, and smooth muscle cell loss. Conversely, overexpression of CCN3 mitigated both elastase- and angiotensin II-induced AAA formation in mice. BM transplantation experiments suggested that the AAA phenotype of CCN3-deficient mice is intrinsic to the vasculature, as AAA was not exacerbated in WT animals that received CCN3-deficient BM and WT BM did not reduce AAA severity in CCN3-deficient mice. Genetic and pharmacological approaches implicated the ERK1/2 pathway as a critical regulator of CCN3-dependent AAA development. Together, these results demonstrate that CCN3 is a nodal regulator in AAA biology and identify CCN3 as a potential therapeutic target for vascular disease.

Background: Atherosclerosis and its complications (myocardial infarction, stroke, peripheral vascular disease) are the major cause of morbidity and mortality in developed countries. Despite considerable efforts, the underlying pathomechanisms remain incompletely understood. In this study, we examined the role of a matricellular protein termed CCN3 in the pathogenesis of atherosclerosis. Methods and Results: To investigate whether CCN3 deficiency affects the development of atherosclerosis, control (ApoE-/-) and CCN3/ApoE double knockout mice were subjected to high fat diet feeding. In response to 16-week high fat diet feeding, the aortas of CCN3/ApoE double knockout (DKO) mice demonstrated exquisite susceptibility to atherosclerosis formation as evidenced by significantly increased size of aortic lipid-rich plaques in aortic roots, arch, thoracic and abdominal aorta. Concomitant with this, the atherosclerosis phenotype of DKO mice was manifested as follows: (1) a profoundly enhanced immune cell infiltration; (2) significantly increased expression of inflammatory markers; (3) heightened reactive oxygen species generation. Next, to address the cellular contributor(s) within or outside of the vessel wall responsible for the atherosclerosis phenotype, we performed reciprocal bone marrow transplantation (BMT) experiments. Transplantation of DKO bone marrow to ApoE-/- mice resulted in an increase of atherosclerosis formation, while transplantation of ApoE-/- marrow to DKO mice caused a reduction of atherosclerosis. These results indicate CCN3 deficiency in the bone marrow plays a major role in the development of atherosclerosis. Mechanistically, our cell-based studies in isolated macrophages demonstrated that CCN3 deficiency leads to an increase of lipid uptake and foam cell formation, an effect attributed to the modulation of key factors (e.g., increase of CD36, decrease of ABCG1) involved in lipoprotein transport. Conclusion: These results demonstrate bone marrow-derived CCN3 as an essential regulator of atherosclerosis and suggest the potential for future therapeutic strategies by manipulating CCN3 levels.

The 8th international workshop on the CCN family of genes was held for a second time in Nice, from November 3rd to 8th, 2015. Under particularly sunny and warm weather everyone enjoyed the charms of the Mediterranean coastline.

CCN family proteins 2 and 3 (CCN2 and CCN3) belong to the CCN family of proteins, all having a high level of structural similarity. It is widely known that CCN2 is a profibrotic molecule that mediates the development of fibrotic disorders in many different tissues and organs. In contrast, CCN3 has been recently suggested to act as an anti-fibrotic factor in several tissues. This CCN3 action was shown earlier to be exerted by the repression of the CCN2 gene expression in kidney tissue, whereas different findings were obtained for liver cells. Thus, the molecular action of CCN3 yielding its anti-fibrotic effect is still controversial. Here, using a general model of fibrosis, we evaluated the effect of CCN3 overexpression on the gene expression of all of the CCN family members, as well as on that of fibrotic marker genes. As a result, repression of CCN2 gene expression was modest, while type I collagen and α-smooth muscle actin gene expression was prominently repressed. Interestingly, not only CCN2, but also CCN4 gene expression showed a decrease upon CCN3 overexpression. These findings indicate that fibrotic gene induction is under the control of a complex molecular network conducted by CCN family members functioning together.