CD44 Is Involved in Tumor Angiogenesis; an Activation Antigen on Human Endothelial Cells

Griffioen, Arjan W.; Coenen, Marieke J.H.; Damen, Cora A.; Hellwig, Sandra M.M.; Weering, David H.J. van; Vooys, Wim; Blijham, Geert H.; Groenewegen, Gerard

doi:10.1182/blood.v90.3.1150

Cited by 128 publications

(49 citation statements)

References 35 publications

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“…71 CD44 is one of the key mediators of EC adhesion through binding to HA and other ECM components fibronectin, collagen, etc. 5,10 The increase in CD44 expression on tumor-associated vessels can enable EC adhesion to ECM components and facilitate neovascularization in the tumor context, 13,34 which is consistent with a putative role of HA in the induction of new vessel formation. 72 Additionally, CD44 can also potentiate the adhesion of cancer cells and leukocytes onto ECs, [73][74][75] facilitating cancer cell extravasation and leukocyte infiltration, which, along with accelerated angiogenesis, may aggravate cancer progression and metastasis.…”

Section: Cd44 In Tumor Angiogenesissupporting

confidence: 54%

“…Cancer led to approximately 9.6 million deaths worldwide in 2018 and is the second leading cause of death. 33 CD44 is highly expressed in cancer cells and cancer-associated ECs, 3,[34][35][36] and its expression has been observed to be associated with poor prognosis for many cancer types, including colorectal carcinoma, infiltrating ductal carcinoma, gastric adenocarcinoma, bladder cancer, head and neck cancer. [37][38][39][40][41][42][43] Although CD44 is widely recognized as a cancer stem marker 3,44 and promotes cancer progression and metastasis by regulating cancer cell stemness, 3,44,45 survival, [46][47][48] proliferation, [47][48][49] and adhesive and invasive properties, [50][51][52][53] the protumorigenic effects of CD44, at least partially, rely on its tumor angiogenesis-promoting activities.…”

Section: Cd44 In Tumor Angiogenesismentioning

confidence: 99%

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The role of CD44 in pathological angiogenesis

Chen

Zhang

et al. 2020

FASEB j.

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Angiogenesis is required for normal development and occurs as a pathological step in a variety of disease settings, such as cancer, ocular diseases, and ischemia. Recent studies have revealed the role of CD44, a widely expressed cell surface adhesion molecule, in promoting pathological angiogenesis and the development of its associated diseases through its regulation of diverse function of endothelial cells, such as proliferation, migration, adhesion, invasion, and communication with the microenvironment. Conversely, the absence of CD44 expression or inhibition of its function impairs pathological angiogenesis and disease progression. Here, we summarize the current understanding of the roles of CD44 in pathological angiogenesis and the underlying cellular and molecular mechanisms.

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Section: Cd44 In Tumor Angiogenesissupporting

confidence: 54%

Section: Cd44 In Tumor Angiogenesismentioning

confidence: 99%

The role of CD44 in pathological angiogenesis

Chen

Zhang

et al. 2020

FASEB j.

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“…All adhesion molecules identified in this screen appeared to be overexpressed in tubular MVEC. CD44 and CD146 have been reported recently as markers for angiogenically active tumor endothelium [31,32]. Antagonism of PECAM‐1 function with a blocking antibody leads to inhibition of in vitro tube formation of endothelial cells on collagen gels [33].…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression by endothelial cells in distinct angiogenic states

Glienke¹,

Schmitt²,

Pilarsky³

et al. 2000

European Journal of Biochemistry

121

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Angiogenesis is a complex process that can be regarded as a series of sequential events comprising a variety of tissue cells. The major problem when studying angiogenesis in vitro is the lack of a model system mimicking the various aspects of the process in vivo. In this study we have used two in vitro models, each representing different and distinct aspects of angiogenesis. Differentially expressed genes in the two culture forms were identified using the suppression subtractive hybridization technique to prepare subtracted cDNA libraries. This was followed by a differential hybridization screen to pick up overexpressed clones. Using comparative multiplex RT-PCR we confirmed the differential expression and showed differences up to 14-fold. We identified a broad range of genes already known to play an important role during angiogenesis like Flt1 or TIE2. Furthermore several known genes are put into the context of endothelial cell differentiation, which up to now have not been described as being relevant to angiogenesis, like NrCAM, Claudin14, BMP-6, PEA-15 and PINCH. With ADAMTS4 and hADAMTS1/METH-1 we further extended the set of matrix metalloproteases expressed and regulated by endothelial cells.Keywords: differential gene expression; MVEC; angiogenesis; suppression subtractive hybridization.Angiogenesis, the formation of new capillaries from preexisting blood vessels, plays a crucial role in a wide range of normal and pathological processes, and is necessary for the continous growth of solid tumors [1,2]. Angiogenesis takes not place in a single step, but is a complex sequential process that relies on a controled cross-talk between endothelial cells and the surrounding avascular environment [2,3]. Upon activation by growth factors or cytokines, endothelial cells start to degrade the surrounding extracellular matrix and invade the avascular tissue. The tight endothelial cell-cell adhesion is disrupted, the cells start to proliferate and migrate into the avascular environment. Finally they stop proliferating and differentiate to tubular structures (reviewed in [3]). Most recent studies have focused on the effect of specific growth factors and cytokines secreted by non endothelial cells on angiogenesis, but little is known about the sequential events taking place in the activated endothelial cells during the formation of new blood vessels.In this work we chose a model system where human microvascular endothelial cells (MVEC) are cultured on a gel composed of extracted basement membrane derived from mouse Engelbreth±Holm±Swarm sarcoma (matrigel) [4]. When seeded at a certain density the cells stop proliferating and virtually all cells are induced rapidly to form capillary-like, lumen containing structures [4,5]. These cells were compared against nondifferentiating, proliferating MVEC again representing an important step during the formation of new blood vessels [2,3]. The advantage of these culture systems is that they can be performed with one and the same cell type resulting in two different homogenous populatio...

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“…At present, it is widely recognized as a pleiotropic molecule expressed by stem cells and involved in tumor metastasis [ 12 , 13 ]. It is described to be a marker of epithelial-to-mesenchymal transition and also of tumor endothelium [ 14 ]. The main ligand for CD44 is hyaluronic acid.…”

Section: Introductionmentioning

confidence: 99%

CD44 enhances tumor aggressiveness by promoting tumor cell plasticity

et al. 2015

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Aggressive tumor cells can obtain the ability to transdifferentiate into cells with endothelial features and thus form vasculogenic networks. This phenomenon, called vasculogenic mimicry (VM), is associated with increased tumor malignancy and poor clinical outcome. To identify novel key molecules implicated in the process of vasculogenic mimicry, microarray analysis was performed to compare gene expression profiles of aggressive (VM+) and non-aggressive (VM−) cells derived from Ewing sarcoma and breast carcinoma. We identified the CD44/c-Met signaling cascade as heavily relevant for vasculogenic mimicry. CD44 was at the center of this cascade, and highly overexpressed in aggressive tumors. Both CD44 standard isoform and its splice variant CD44v6 were linked to increased aggressiveness in VM. Since VM is most abundant in Ewing sarcoma tumors functional analyses were performed in EW7 cells. Overexpression of CD44 allowed enhanced adhesion to its extracellular matrix ligand hyaluronic acid. CD44 expression also facilitated the formation of vasculogenic structures in vitro, as CD44 knockdown experiments repressed migration and vascular network formation. From these results and the observation that CD44 expression is associated with vasculogenic structures and blood lakes in human Ewing sarcoma tissues, we conclude that CD44 increases aggressiveness in tumors through the process of vasculogenic mimicry.

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CD44 Is Involved in Tumor Angiogenesis; an Activation Antigen on Human Endothelial Cells

Cited by 128 publications

References 35 publications

The role of CD44 in pathological angiogenesis

The role of CD44 in pathological angiogenesis

Differential gene expression by endothelial cells in distinct angiogenic states

CD44 enhances tumor aggressiveness by promoting tumor cell plasticity

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