Chondroitin sulfate proteoglycan 4 (CSPG4) increases invasion of recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma by modifying TGFß signaling.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin-blistering disorder often progressing to metastatic cutaneous squamous cell carcinoma (cSCC) at chronic wound sites. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell-surface proteoglycan that is an oncoantigen in multiple malignancies, where it modulates oncogenic signaling, drives epithelial-to-mesenchymal transition (EMT), and enables cell motility. OBJECTIVES: To evaluate CSPG4 expression and function in RDEB-cSCC. METHODS: RDEB-cSCC cell lines were used to assess CSPG4-dependent changes in invasive potential, TGFß1-stimulated signal activation, and clinically relevant cytopathology metrics in an in vitro full-thickness tumor model. CSPG4 expression in RDEB-cSCC and non-RDEB cSCC tumors was analyzed via immunohistochemistry and single-cell RNA sequencing (scRNA-seq), respectively. RESULTS: Inhibiting CSPG4 expression reduced invasive potential in multiple RDEB-cSCC cell lines and altered membrane-proximal TGFß signal activation through changes in SMAD3 phosphorylation. CSPG4 expression was uniformly localized to basal-layer keratinocytes in fibrotic RDEB skin and tumor cells at the tumor/stroma interface at the invasive front in RDEB-cSCC tumors in vivo. Analysis of published scRNA-seq data revealed that CSPG4 expression was correlated with an enhanced EMT transcriptomic signature in cells at the tumor/stroma interface of non-RDEB cSCC tumors. Cytopathological metrics, like nucleus:cell area ratio, were influenced by CSPG4 expression in in vitro tumor models. CONCLUSIONS: We determined that CSPG4 expression in RDEB-cSCC cell lines enhanced invasive potential. Mechanistically, CSPG4 was found to enhance membrane-proximal TGFß-stimulated signaling through SMAD3, which is a key mediator of EMT in RDEB-cSCC. The implication of these studies is that CSPG4 may represent a therapeutic target that can be leveraged for clinical management in patients with RDEB-cSCC.

RHAMM regulates MMTV-PyMT-induced lung metastasis by connecting STING-dependent DNA damage sensing to interferon/STAT1 pro-apoptosis signaling.

BACKGROUND: RHAMM is a multifunctional protein that is upregulated in breast tumors, and the presence of strongly RHAMM+ve cancer cell subsets associates with elevated risk of peripheral metastasis. Experimentally, RHAMM impacts cell cycle progression and cell migration. However, the RHAMM functions that contribute to breast cancer metastasis are poorly understood. METHODS: We interrogated the metastatic functions of RHAMM using a loss-of-function approach by crossing the MMTV-PyMT mouse model of breast cancer susceptibility with Rhamm-/- mice. In vitro analyses of known RHAMM functions were performed using primary tumor cell cultures and MMTV-PyMT cell lines. Somatic mutations were identified using a mouse genotyping array. RNA-seq was performed to identify transcriptome changes resulting from Rhamm-loss, and SiRNA and CRISPR/Cas9 gene editing was used to establish cause and effect of survival mechanisms in vitro. RESULTS: Rhamm-loss does not alter initiation or growth of MMTV-PyMT-induced primary tumors but unexpectedly increases lung metastasis. Increased metastatic propensity with Rhamm-loss is not associated with obvious alterations in proliferation, epithelial plasticity, migration, invasion or genomic stability. SNV analyses identify positive selection of Rhamm-/- primary tumor clones that are enriched in lung metastases. Rhamm-/- tumor clones are characterized by an increased ability to survive with ROS-mediated DNA damage, which associates with blunted expression of interferon pathway and target genes, particularly those implicated in DNA damage-resistance. Mechanistic analyses show that ablating RHAMM expression in breast tumor cells by siRNA knockdown or CRISPR-Cas9 gene editing blunts interferon signaling activation by STING agonists and reduces STING agonist-induced apoptosis. The metastasis-specific effect of RHAMM expression-loss is linked to microenvironmental factors unique to tumor-bearing lung tissue, notably high ROS and TGFB levels. These factors promote STING-induced apoptosis of RHAMM+ve tumor cells to a significantly greater extent than RHAMM-ve comparators. As predicted by these results, colony size of Wildtype lung metastases is inversely related to RHAMM expression. CONCLUSION: RHAMM expression-loss blunts STING-IFN signaling, which offers growth advantages under specific microenvironmental conditions of lung tissue. These results provide mechanistic insight into factors controlling clonal survival/expansion of metastatic colonies and has translational potential for RHAMM expression as a marker of sensitivity to interferon therapy.

Receptor for hyaluronan-mediated motility (RHAMM) defines an invasive niche associated with tumor progression and predicts poor outcomes in breast cancer patients.

Breast cancer invasion and metastasis result from a complex interplay between tumor cells and the tumor microenvironment (TME). Key oncogenic changes in the TME include aberrant synthesis, processing, and signaling of hyaluronan (HA). Hyaluronan-mediated motility receptor (RHAMM, CD168; HMMR) is an HA receptor enabling tumor cells to sense and respond to this aberrant TME during breast cancer progression. Previous studies have associated RHAMM expression with breast tumor progression; however, cause and effect mechanisms are incompletely established. Focused gene expression analysis of an internal breast cancer patient cohort confirmed that increased RHAMM expression correlates with aggressive clinicopathological features. To probe mechanisms, we developed a novel 27-gene RHAMM-related signature (RRS) by intersecting differentially expressed genes in lymph node (LN)-positive patient cases with the transcriptome of a RHAMM-dependent model of cell transformation, which we validated in an independent cohort. We demonstrate that the RRS predicts for poor survival and is enriched for cell cycle and TME-interaction pathways. Further analyses using CRISPR/Cas9-generated RHAMM-/- breast cancer cells provided direct evidence that RHAMM promotes invasion in vitro and in vivo. Immunohistochemistry studies highlighted heterogeneous RHAMM protein expression, and spatial transcriptomics associated the RRS with RHAMM-high microanatomic foci. We conclude that RHAMM upregulation leads to the formation of 'invasive niches', which are enriched in RRS-related pathways that drive invasion and could be targeted to limit invasive progression and improve patient outcomes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

HUNDRED YEARS OF THE PSYCHOANALYTIC PROGRESSIVE MENTAL HEALTH MOVEMENT.

Beginning in 1920 and in keeping with Freud's sustained encouragement, the first two generations of European psychoanalysts initiated a progressive mental health movement by offering very low cost and free psychoanalytic services that were in harmony with Austrian social democratic and socialist political leaders' commitment to societal reforms in light of the economic and social inequities after the First World War. This synthesis of biographical and autobiographical accounts of early Freudian, Ego Psychology and Neo-Freudian theorists' contributions highlights their consideration of the effects of social injustice as central challenges to the development of psychological growth.

FOXA1 prevents nutrients deprivation induced autophagic cell death through inducing loss of imprinting of IGF2 in lung adenocarcinoma.

Lung cancer remains one of the most common malignancies and the leading cause of cancer-related death worldwide. Forkhead box protein A1 (FOXA1) is a pioneer factor amplified in lung adenocarcinoma (LUAD). However, its role in LUAD remains elusive. In this study, we found that expression of FOXA1 enhanced LUAD cell survival in nutrients deprived conditions through inhibiting autophagic cell death (ACD). FOXA1 bound to the imprinting control region of insulin-like growth factor 2 (IGF2) and interacted with DNA methyltransferase 1 (DNMT1), leading to initiation of DNMT1-mediated loss of imprinting (LOI) of IGF2 and autocrine of IGF2. Blockage of IGF2 and its downstream insulin-like growth factor 1 receptor (IGF1R) abolished the protective effect of FOXA1 on LUAD cells in nutrients deprived conditions. Furthermore, FOXA1 suppressed the expression of the lysosomal enzyme glucocerebrosidase 1 (GBA1), a positive mediator of ACD, through ubiquitination of GBA1 enhanced by IGF2. Notably, FOXA1 expression in A549 cells reduced the efficacy of the anti-angiogenic drug nintedanib to inhibit xenograft tumor growth, whereas a combination of nintedanib with IGF1R inhibitor linsitinib or mTORC1 inhibitor rapamycin enhanced tumor control. Clinically, high expression level of FOXA1 protein was associated with unfavorable prognosis in LUAD patients of advanced stage who received bevacizumab treatment. Our findings uncovered a previously unrecognized role of FOXA1 in mediating loss of imprinting of IGF2, which confer LUAD cells enhanced survival ability against nutrients deprivation through suppressing autophagic cell death.

Co-Expression and Combined Prognostic Value of CSPG4 and PDL1 in TP53-Aberrant Triple-Negative Breast Cancer.

Background: In triple-negative breast cancer (TNBC), PDL1/PD1-directed immunotherapy is effective in less than 20% of patients. In our preliminary study, we have found CSPG4 to be highly expressed together with PDL1 in TNBCs, particularly those harboring TP53 aberrations. However, the clinical implications of co-expressed CSPG4 and PDL1 in TNBCs remain elusive. Methods: A total of 85 advanced TNBC patients treated in the Hunan Cancer Hospital between January 2017 and August 2019 were recruited. The expressions of CSPG4 and PDL1 in TNBC tissues were investigated using immunohistochemistry (IHC). The RNA-seq dataset from the TCGA-BRCA project was further used to analyze the mRNA expression of CSPG4 and PDL1 in TP53-aberrant TNBCs. Cox proportional hazards model and Kaplan-Meier curves with Logrank test was used to analyze the effects of CSPG4 and PDL1 on survival. TNBC cell lines were further used to investigate the molecular mechanism that were involved. Results: TP53 aberrations occurred in more than 50% of metastatic TNBCs and were related to higher tumor mutation burden (TMB). In TCGA-BRCA RNA-seq dataset analysis, both CSPG4 and PDL1 levels were high in TNBCs, especially in TP53-aberrant TNBCs. IHC assay showed nearly 60% of advanced TNBCs to be CSPG4-positive and about 25% to be both CSPG4-positive and PDL1-positive. The levels of CSPG4 and PDL1 were high in TNBC cell lines as revealed by flow cytometry and immunoblotting compared with non-TNBC cells. Univariate Cox regression analysis indicated that CSPG4 positivity was a significant risk factor for progression-free survival in metastatic TNBCs, with a hazard ratio (HR) of 2.26 (P = 0.05). KM curves with Logrank test also identified high level of CSPG4 as a significant risk factor for overall survival in advanced breast cancers in TCGA-BRCA samples (P = 0.02). The immunoblotting assays showed that EMT-related pathways were involved in CSPG4-mediated invasion. Conclusions: CSPG4 expression level is associated with PDL1 positivity in TP53-aberrant TNBC cells. Patients with CSPG4 expression have poor treatment response and poor overall survival. Co-expressed CSPG4 and PDL1 may have an important prognostic value and provide new therapeutic targets in TNBC patients. CSPG4 might mediate tumor invasion and PDL1 overexpression through EMT-related pathway.

Chondroitin sulfate proteoglycan 4, a targetable oncoantigen that promotes ovarian cancer growth, invasion, cisplatin resistance and spheroid formation.

Epithelial ovarian cancer (EOC) is a highly heterogeneous disease encompassing several distinct molecular subtypes and clinical entities. Despite the initial success of surgical debulking and adjuvant chemotherapy, recurrence with chemotherapy resistant tumors is common in patients with EOC and leads to poor overall survival. The extensive genetic and phenotypic heterogeneity associated with ovarian cancers has hindered the identification of effective prognostic and predictive biomarkers in EOC patients. In the current studies, we identify a tumor cell surface oncoantigen, chondroitin sulfate proteoglycan 4 (CSPG4), as an independent risk factor for decreased survival of patients with EOC. Our results show that CSPG4 promotes EOC cell invasion, cisplatin resistance and spheroid formation in vitro and tumor expansion in vivo. Mechanistically, spheroid formation and tumor cell invasion are due to CSPG4-stimulated expression of the mesenchymal transcription factor ZEB1. Furthermore, we have developed a novel monoclonal anti-CSGP4 antibody against the juxtamembrane domain of the core protein that limits CSPG4-stimulated ZEB1 expression, tumor cell invasion and promotes EOC apoptosis within spheroid cultures. We therefore propose that CSPG4 expression drives phenotypic heterogeneity and malignant progression in EOC tumors. These studies further demonstrate that CSPG4 expression levels are a potential diagnostic biomarker in EOC and indicate that targeting cells which express this oncoantigen could limit recurrence and improve outcomes in patients with EOC.

RHAMM Is a Multifunctional Protein That Regulates Cancer Progression.

The functional complexity of higher organisms is not easily accounted for by the size of their genomes. Rather, complexity appears to be generated by transcriptional, translational, and post-translational mechanisms and tissue organization that produces a context-dependent response of cells to specific stimuli. One property of gene products that likely increases the ability of cells to respond to stimuli with complexity is the multifunctionality of expressed proteins. Receptor for hyaluronan-mediated motility (RHAMM) is an example of a multifunctional protein that controls differential responses of cells in response-to-injury contexts. Here, we trace its evolution into a sensor-transducer of tissue injury signals in higher organisms through the detection of hyaluronan (HA) that accumulates in injured microenvironments. Our goal is to highlight the domain and isoform structures that generate RHAMM's function complexity and model approaches for targeting its key functions to control cancer progression.

The role of psychopathology in the relationship between history of maltreatment and suicide attempts among children and adolescent inpatients.

BACKGROUND: This retrospective chart review study investigates the relationship between the history of various forms of abuse and the presence of mood disorders and psychotic symptoms in predicting suicide attempts among psychiatrically hospitalized children and adolescents. METHOD: A multi-mediation analysis was conducted with an archival dataset of 101 children and adolescents hospitalized predominantly for mood disorders and bipolar disorders with and without history of psychotic symptoms. RESULTS: Results showed that history of suicide attempts was directly associated with physical abuse and indirectly associated with sexual abuse (mediated by bipolar disorders). Emotional abuse was also indirectly related to history of suicide attempts, mediated by mood disorders for boys, and by psychotic symptoms for girls. CONCLUSIONS: This study is among the first to differentiate the unique effects of different types of early maltreatment on psychopathology, particularly mood disorders and psychotic symptoms, and histories of suicide attempts in psychiatrically hospitalized children and youth. KEY PRACTITIONER MESSAGE: Little is known about the relationships between histories of maltreatment, psychopathology, and suicide (considered simultaneously) among hospitalized children and adolescents. Different forms of abuse are associated with distinct psychopathology symptoms, and in turn, risk for suicide attempts. Only physical abuse is directly related to a history of suicide attempts, while sexual and emotional abuse are indirectly related (mediated by mood disorders and psychotic symptoms). These risk pathways are partly distinct for girls and boys. Identifying unique and cumulated risk factors can help prevent suicidality among hospitalized youth.

Erratum: Witschen, P.M., et al. Tumor Cell Associated Hyaluronan-CD44 Signaling Promotes Pro-Tumor Inflammation in Breast Cancer. Cancers 2020, 12, 1325.

The authors wish to make the following corrections to this paper [...].

Tumor Cell Associated Hyaluronan-CD44 Signaling Promotes Pro-Tumor Inflammation in Breast Cancer.

Cancer has been conceptualized as a chronic wound with a predominance of tumor promoting inflammation. Given the accumulating evidence that the microenvironment supports tumor growth, we investigated hyaluronan (HA)-CD44 interactions within breast cancer cells, to determine whether this axis directly impacts the formation of an inflammatory microenvironment. Our results demonstrate that breast cancer cells synthesize and fragment HA and express CD44 on the cell surface. Using RNA sequencing approaches, we found that loss of CD44 in breast cancer cells altered the expression of cytokine-related genes. Specifically, we found that production of the chemokine CCL2 by breast cancer cells was significantly decreased after depletion of either CD44 or HA. In vivo, we found that CD44 deletion in breast cancer cells resulted in a delay in tumor formation and localized progression. This finding was accompanied by a decrease in infiltrating CD206+ macrophages, which are typically associated with tumor promoting functions. Importantly, our laboratory results were supported by human breast cancer patient data, where increased HAS2 expression was significantly associated with a tumor promoting inflammatory gene signature. Because high levels of HA deposition within many tumor types yields a poorer prognosis, our results emphasize that HA-CD44 interactions potentially have broad implications across multiple cancers.

Cell-specific expression of the transcriptional regulator RHAMM provides a timing mechanism that controls appropriate wound re-epithelialization.

Prevention of aberrant cutaneous wound repair and appropriate regeneration of an intact and functional integument require the coordinated timing of fibroblast and keratinocyte migration. Here, we identified a mechanism whereby opposing cell-specific motogenic functions of a multifunctional intracellular and extracellular protein, the receptor for hyaluronan-mediated motility (RHAMM), coordinates fibroblast and keratinocyte migration speed and ensures appropriate timing of excisional wound closure. We found that, unlike in WT mice, in Rhamm-null mice, keratinocyte migration initiates prematurely in the excisional wounds, resulting in wounds that have re-surfaced before the formation of normal granulation tissue, leading to a defective epidermal architecture. We also noted aberrant keratinocyte and fibroblast migration in the Rhamm-null mice, indicating that RHAMM suppresses keratinocyte motility but increases fibroblast motility. This cell context-dependent effect resulted from cell-specific regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) activation and expression of a RHAMM target gene encoding matrix metalloprotease 9 (MMP-9). In fibroblasts, RHAMM promoted ERK1/2 activation and MMP-9 expression, whereas in keratinocytes, RHAMM suppressed these activities. In keratinocytes, loss of RHAMM function or expression promoted epidermal growth factor receptor-regulated MMP-9 expression via ERK1/2, which resulted in cleavage of the ectodomain of the RHAMM partner protein CD44 and thereby increased keratinocyte motility. These results identify RHAMM as a key factor that integrates the timing of wound repair by controlling cell migration.

SEMA4C is a novel target to limit osteosarcoma growth, progression, and metastasis.

Semaphorins, specifically type IV, are important regulators of axonal guidance and have been increasingly implicated in poor prognoses in a number of different solid cancers. In conjunction with their cognate PLXNB family receptors, type IV members have been increasingly shown to mediate oncogenic functions necessary for tumor development and malignant spread. In this study, we investigated the role of semaphorin 4C (SEMA4C) in osteosarcoma growth, progression, and metastasis. We investigated the expression and localization of SEMA4C in primary osteosarcoma patient tissues and its tumorigenic functions in these malignancies. We demonstrate that overexpression of SEMA4C promotes properties of cellular transformation, while RNAi knockdown of SEMA4C promotes adhesion and reduces cellular proliferation, colony formation, migration, wound healing, tumor growth, and lung metastasis. These phenotypic changes were accompanied by reductions in activated AKT signaling, G1 cell cycle delay, and decreases in expression of mesenchymal marker genes SNAI1, SNAI2, and TWIST1. Lastly, monoclonal antibody blockade of SEMA4C in vitro mirrored that of the genetic studies. Together, our results indicate a multi-dimensional oncogenic role for SEMA4C in metastatic osteosarcoma and more importantly that SEMA4C has actionable clinical potential.

ΔNp63α is a super enhancer-enriched master factor controlling the basal-to-luminal differentiation transcriptional program and gene regulatory networks in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) originates via malignant transformation of the pseudostratified nasopharyngeal epithelium, composed of basal and luminal cells. Super enhancers (SEs) are large clusters of cis-elements involved in the regulation of gene expression through epigenetic regulatory mechanisms. In this study, we demonstrated that basal cell-specific proteins are highly expressed, whereas luminal cell proteins are downregulated in NPC, implying a perturbation of basal-to-luminal differentiation during NPC development. We characterized NPC cell models according to different molecular signatures associated with their differentiation status and found that distinct SE landscapes are tightly associated with basal or luminal-like molecular signatures in NPC cells. Furthermore, the transcription of ΔNP63α, a prominent isoform of TP63, was found to be driven by SEs in NPC cells. Data from chromatin immunoprecipitation (ChIP)-sequencing showed that ΔNP63α largely occupied regions of SEs associated with basal cell-specific genes. Silencing of ΔNP63α led to a loss of H3K27ac occupancy at basal-type SEs and triggered a basal-to-luminal gene expression signature switch, suggesting that ΔNP63α is a master factor contributing to the perturbation of luminal differentiation. Integrative transcriptomics analysis also revealed that ΔNP63α acts as a core factor involved in the dysregulation of gene expression in NPC. Furthermore, ΔNP63α enhanced EGF-stimulated NF-κB activation in NPC cells by activating SE-mediated EGFR transcription. Finally, depletion of ΔNP63α in NPC cells induced robust growth inhibition of NPC cells in vitro and in vivo. Our data revealed that ΔNP63α-dependent SE reprogramming contributes to the blockade of luminal differentiation and uncontrolled proliferation in NPC.

Chondroitin sulfate proteoglycan 4 enhanced melanoma motility and growth requires a cysteine in the core protein transmembrane domain.

Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan that enhances malignant potential in melanoma and several other tumor types. CSPG4 functions as a transmembrane scaffold in melanoma cells to activate oncogenic signaling pathways such as focal adhesion kinase (FAK) and extracellular signal regulated kinases 1,2, that control motility, invasion and anchorage independent growth. Here, we demonstrate that CSPG4 promotes directional motility and anchorage independent growth of melanoma cells by organizing and positioning a signaling complex containing activated FAK to lipid rafts within the plasma membrane of migrating cells. This FAK-containing signal transduction platform, which consists of syntenin-1, active Src and caveolin-1 requires the cytoplasmic domain of CSPG4 for assembly. Enhanced directional motility promoted by this complex also requires a CSPG4 transmembrane cysteine residue C2230. Substituting C2230 with alanine (CSPG4) still permits assembly of the signaling complex, however Src remains in an inactive state. CSPG4 also fails to promote anchorage independent growth and activation of extracellular signal regulated kinases 1,2. Therapies that target the transmembrane domain of CSPG4 could be a novel strategy for limiting progression by disrupting its function as a compartmentalized motogenic and growth-promoting oncogenic signaling node.

Corrigendum: Hyaluronan, Cancer-Associated Fibroblasts and the Tumor Microenvironment in Malignant Progression.

[This corrects the article DOI: 10.3389/fcell.2018.00048.].

Hyaluronan, Cancer-Associated Fibroblasts and the Tumor Microenvironment in Malignant Progression.

This review summarizes the roles of CAFs in forming a "cancerized" fibrotic stroma favorable to tumor initiation and dissemination, in particular highlighting the functions of the extracellular matrix component hyaluronan (HA) in these processes. The structural complexity of the tumor and its host microenvironment is now well appreciated to be an important contributing factor to malignant progression and resistance-to-therapy. There are multiple components of this complexity, which include an extensive remodeling of the extracellular matrix (ECM) and associated biomechanical changes in tumor stroma. Tumor stroma is often fibrotic and rich in fibrillar type I collagen and hyaluronan (HA). Cancer-associated fibroblasts (CAFs) are a major source of this fibrotic ECM. CAFs organize collagen fibrils and these biomechanical alterations provide highways for invading carcinoma cells either under the guidance of CAFs or following their epithelial to mesenchymal transition (EMT). The increased HA metabolism of a tumor microenvironment instructs carcinoma initiation and dissemination by performing multiple functions. The key effects of HA reviewed here are its role in activating CAFs in pre-malignant and malignant stroma, and facilitating invasion by promoting motility of both CAFs and tumor cells, thus facilitating their invasion. Circulating CAFs (cCAFs) also form heterotypic clusters with circulating tumor cells (CTC), which are considered to be pre-cursors of metastatic colonies. cCAFs are likely required for extravasation of tumors cells and to form a metastatic niche suitable for new tumor colony growth. Therapeutic interventions designed to target both HA and CAFs in order to limit tumor spread and increase response to current therapies are discussed.

In vitro elucidation of the role of pericellular matrix in metastatic extravasation and invasion of breast carcinoma cells.

Numerous studies have demonstrated the importance of altered hyaluronan metabolism to malignant progression of multiple tumor types, including breast carcinomas. Increased hyaluronan (HA) metabolism in the stroma of primary tumors promotes activation of oncogenic signaling pathways that impact tumor initiation, growth, and invasion. Carcinoma cell synthesis and assembly of HA-rich pericellular matrices induces a stromal-independent phenotype, which is associated with cancer progression. Although the pro-tumorigenic role of stromal HA is well established, a novel but unexplored hypothesis is that carcinoma cell-associated HA pericellular matrices promote metastasis of circulating tumor cells. Here, we report the development of an in vitro assay that employs microfluidic techniques to directly measure the importance of an HA-rich pericellular matrix in the entry of carcinoma cells into ectopic sites. This model provides the capability to visualize specific steps in metastasis, which is difficult using animal models. The results show that the presence of a HA-rich pericellular matrix correlates to the invasive and metastatic potential of breast carcinoma cells. Furthermore, enzymatic removal or pharmacologic inhibition of HA synthesis significantly inhibits carcinoma cell extravasation and invasion in this model system. These results implicate pericellular HA-rich carcinoma cell associated pericellular matrices in colonization of ectopic sites by circulating tumor cells and support specific targeting of this matrix to limit metastasis in patients.

The NOR1/OSCP1 proteins in cancer: from epigenetic silencing to functional characterization of a novel tumor suppressor.

NOR1 (Oxidored-nitro domain-containing protein 1), also known as OSCP1, was first identified in nasopharyngeal carcinoma (NPC) cells in 2003. NOR1 is evolutionarily conserved among species with its expression is restricted to brain, testis and respiratory epithelial cells. NOR1 was downregulated in NPC and the downregulation associates with poor prognosis. Previous study demonstrated that hypermethylation of NOR1 promoter was observed in NPC and hematological malignancies, which has been believed to be the main epigenetic cause for NOR1 silencing in these cancers. Recently, the NOR1 tumor suppressor status has been fully established. NOR1 inhibited cancer cell growth by disturbing tumor cell energe metabolism. NOR1 also promote tumor cells apoptosis in oxidative stress and hypoxia by inhibition of stress induced autophagy. Moreover, NOR1 suppressed cancer cell epithelial-mesenchymal transition, invasion and metastasis via activation of FOXA1/HDAC2-slug regulatory network. Deciphering the molecular mechanisms underlying NOR1 mediated tumor suppressive role would be helpful to a deeper understanding of carcinogenesis and, furthermore, to the development of new therapeutic approaches. Here we summarize the current knowledge on NOR1 focusing on its expression pattern, epigenetic and genetic association with human cancers and its biological functions. This review will also elucidate the potential application of NOR1/OSCP1 for some human malignancies.