Review article

The role of notch signaling in bone marrow niche Shirin Azizidoost 1, Mehrnoosh Shanaki Bavarsad 2, Mahsa Shanaki Bavarsad 1, Saeid Shahrabi 3, Kaveh Jaseb 1, Fakher Rahim4, Mohammad Shahjahani 5, Fakhredin Saba 5, Mahdi Ghorbani 6, Najmaldin Saki 1 1

Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran, 2Clinical Biochemistry Department, Faculty of Medicine, Tehran University of Medical Science, Tehran, Iran, 3Department of Biochemistry and Hematology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran, 4Health Research Institute, Hearing Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran, 5Department of Hematology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran, 6Department of Laboratory Science, Paramedical Faculty, AJA University of Medical Sciences, Tehran, Iran Objective: Bone marrow (BM) niche is a three-dimensional structure composed of a series of cells and it is one of the most controversial topics in hematological malignancies, leukemia, and even metastasis. Here, we review the relationship between Notch signaling and different fates of stem cells and other BM niche cells. Methods: Relevant English-language literature were searched and retrieved from PubMed (2000–2013) using the terms Notch signaling, BM niche, and microRNAs (miRNAs). Discussion: Notch signaling pathway is a signaling system involved in cellular processes such as proliferation, differentiation, and apoptosis. The notch signaling pathway components are associated with interaction between leukemic, metastatic, and normal cells and their microenvironment. miRNAs play an important role in expression and regulation of signaling molecules. It is necessary to evaluate the relationship between aberrant miRNA expression and notch signaling such as miR-128 and miR-30 in glioma and angiogenesis with notch signaling, respectively. Conclusions: Characterizing malignant cells and future studies focus on better understanding the variety of cancers and apoptosis with activated Notch signaling pathway, may remain promising this signaling system as a safe and effective therapeutic target. Keywords: Notch signaling, Hematopoietic stem cell, Mesenchymal stem cell, Bone marrow niche, Metastasis, miRNA

Introduction Bone marrow (BM) stem cell niche is one of the most controversial topics in the hematological malignancies, leukemia, and even metastasis. BM niche is a three-dimensional structure composed of a series of cells, and is locating many important hematopoietic and non-hematopoietic stem cells.1 BM is the place where the blood cells are produced, while BM niche is the starting zone for many hematological malignancies and metastasis site of many cancer cells of other organs. Thus, studying the structure of BM, causes of its malignancy, the reasons for migration of cells of other tissues towards BM, and even drug resistance

Correspondence to: Najmaldin Saki, Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 61357-15794, Iran. najmaldin [email protected]

© W. S. Maney & Son Ltd 2014 DOI 10.1179/1607845414Y.0000000167

of malignant cells in niche are important topics to notice.2 Besides, another vital function of niche is controlling the fate of cells. Therefore, understanding the reactions as well as cellular and molecular mechanisms involved in niche is that important to allow the cells to affect the fate of each other (differentiation induction or inhibition, apoptosis, and inactivation of the cells). The study of cell signaling pathways during cell development has helped the researchers effectively.3 Notch is a cell signaling pathway involved in a wide variety of cellular processes such as apoptosis, differentiation, tissue self-renewal, and migration regulation.4–6 In addition, the above-mentioned roles, Notch plays important roles in development of cancer and tissue metastasis as an oncogene or tumor suppressor.3 Therefore, in this review, we present some concepts about the relationship between signaling of Notch molecule and different fates of stem cells and other cells in BM niche.

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Notch signaling and its effect on BM components Notch is a signaling pathway controlling a wide range of cellular processes including proliferation, apoptosis, tissue self-renewal regulation, differentiation, and maintenance of precursor cells. These are essential functions of Notch signaling pathway in maintaining the normal homeostasis of BM.7 Besides, abnormalities in Notch signaling pathway during the transformation of normal to malignant niche direct the cells towards oncogenes, tissue metastasis, and even human degenerative diseases.3,5 The Notch molecule has four Notch receptors1–4 and five Delta-like 1 ligands, including Dll-1, Dll-3, Dll-4, Jagged-1, and Jagged-2.8 Notch receptor is composed of three parts including extracellular, intracellular, and transmembrane domains with various cellular functions. The process triggering Notch signaling pathway is the release of the intracellular domain of Notch receptor into cytoplasm and its subsequent transport to the nucleus through a proteolytic cut by a gamma-secretase (GS) protein complex. This process is caused by coupling Notch receptor and ligands.5,9 The GS protein complex cut is formed during receptor–ligand

coupling, and the second transmembrane of Notch receptor is the site of this cut. ADAM17/TAEC enzyme complex can also generate cuts in the intracellular domain of Notch (NICD) receptor. The set of events during the above-mentioned two cuts leads to releasing the NICD molecule. NICD forms a complex with any of CSL (CBF-1, suppressor of Hairless, Lag-2), MAML-1, and P300/CβP transcription regulators in the nucleus, as well as inducing expression of downstream Notch transcriptional factors, especially Hes-1 (hairy and enhancer of split1).10 Hes-1 expression is induced by Notch, and plays a role in regulating stem cell characteristics in the niche. Notch signaling has various effects on the main cellular components of BM microenvironment, including hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), osteoclasts, and osteoblasts (Fig. 1).

Osteoblasts Osteoblasts are among BM niche cells derived from MSCs.1 The inductive and inhibitory roles of Notch signaling in the development of osteoblasts have been demonstrated in many studies.11 During

Figure 1 The figure shows the relationship between the main components of BM and Notch signaling pathway.

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osteoblastogenesis, the inhibitory effect of Notch is observed during reaction with Forkhead box transcription factor O (Foxo) 1 and Wnt signaling pathway. These processes inhibits the function of nuclear factor of activated T cells (NFAT) and βcatenin.11 The binding of NICD to runt-related transcription factor 2 (Runx2) has also been noted that inhibits maturing osteoblasts.11,12 The stimulating effect of Notch in differentiation of osteoblasts is induced by bone morphogenetic protein 2 (BMP2).13 In addition, Notch can enhance osteoblastic proliferation by increasing the frequency of SP7 transcription factor.11 Meanwhile, mir-133 and mir-135 are molecules that inhibit Runx2 and BMP-2 functions, respectively, in the osteoblastic differentiation pathway.12 Therefore, it can be concluded that besides controlling MSCs to osteoblasts differentiation by Notch signaling pathway, the short-term and persistent activity of this signaling pathway will result in stimulation and inhibition of osteoblasts.13 In this regard, studies on a murine model of overexpression of the Notch1 intracellular domain have indicated inhibiting the osteoblastic differentiation during osteopenia.14

Osteoclasts Osteoclasts are among BM niche cells derived from macrophage lineages in response to receptor activator of NF-kB ligand (RANKL) and macrophage colonystimulating factor.15 Similar to its role in osteoblasts, the Notch signaling pathway may function as a positive or negative regulator of osteoclastic development.15,16 Deletion of Notch receptors such as Notch1 has been found to increase osteoclastic development.15 It has also been shown that Notch2 and Dll1 are important stimulating factors in the osteoclastogenesis through Notch signaling pathway. Therefore, Notch1 and Jagged-1 are responsible for the inhibitory role of Notch in differentiation of osteoclasts.13 In addition, in osteoclast precursor level, Notch will inhibit the final differentiation of osteoclasts by decreasing the expression of c-Fms.16 It can be concluded that the role of Notch signaling pathway during osteoclastogenesis is dependent on the relationship between the expression of specific Notch ligands and receptors.

Hematopoietic stem cells As an essential regulator of hematopoietic differentiation, Notch is involved in regulating the function and maintaining the phenotype of HSCs.17 Expression of Notch receptors and ligands by HSCs and stromal cells, respectively, terminates the differentiation of HSC during the reaction between the Notch ligands and receptors.18 The hormones are also involved in the regulation of BM niche by interacting

Notch signaling in bone marrow niche

with Notch ligands. In this connection, parathyroid hormone (PTH) increases the expansion of HSCs by increasing the expression of Jagged-1.1,6,19 In addition to the hormonal role in self-renewal of HSCs, interaction between HoxB4 (homeobox B4) and Notch1 also plays a role in increasing the number of these cells.20 Notch signaling in interaction with other signaling pathways, especially Wnt signaling, will lead to β-catenin stabilization in BM stromal cells, and will enhance maintenance and self-renewal of HSC.21 Besides the role of Notch in maintenance of hematopoietic progenitors, deletion of Notch1 alone or Notch1 and Notch2 can lead to increased differentiation of lymphoid HSCs.17 BM vascular niche plays an important role in maintenance of HSCs in association with Notch. Endothelial cells in the niche will lead to reconstitution of hematopoiesis by secreting angiocrine factors such as Notch ligands through replenishment of long-term hematopoietic stem cells (LT-HSCs) pool.21 Components of Notch signaling pathway, including Notch1 are vital for development of embryonic stem cells from endothelial cells. It has been shown that knockdown of the components of this signaling pathway (including blocking the cutting the second intracellular Notch) can lead to decreased repopulation potential of HSC pool.22 Lack of Notch signaling pathway causes impaired maintenance of HSC both in vivo and in vitro.20 In summary, it is now evident that Notch signaling can regulate the specification of HSC such as proliferation, differentiation, and maintenance.

Mesenchymal stem cells These cells are multipotent stem cells with the capacity to differentiate into various cell lines, including osteoblast, cartilage, neural precursors, bone, fat, and other cell types.1 Notch1–3 receptors are identified as MSCs receptors. However, Jagged-1 is the sole ligand significantly expressed in MSCs.23 Studies have indicated the prominent role of Notch signaling in targeted differentiation of MSCs into different cell lines.1,24 In BM, Notch keeps MSCs in an undifferentiated state by reacting with transcription factors and maintaining the pool of mesenchymal progenitors. For example, Notch signaling pathway inhibits osteoblastic differentiation of MSCs by inhibiting Runx2 transcription factor.25 Zanoti showed that overexpression of Notch1 molecule with Prx1 enhancer causes proliferation induction of precursor mesenchymal cells.1 The presence of oxygen affects the differentiation function of MSCs, and its deficiency plays a role in the induction of Notch1 expression during osteogenic differentiation of MSCs. On the other hand, GS inhibitors (GSIs) reduce proliferation of MSCs and increase their differentiation into osteoblasts.26 In hypoxic conditions, Notch inhibits osteogenic differentiation of

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Table 1

Cross-talk between Notch pathway and BM components

Notch pathway component

BM component

Jagged-1, Notch, Notch2

HSC

Notch1-3, Jagged1 Notch, NICD

MSC

Notch1, Notch2, DII1, Jagged-1

Osteoclast

Osteoblast

Involved targets

Cross-talk

Reference

PTH, β-catenin, lymphoid HSC, angiocrine factors Runx2, Prx1 enhancer, HIF-1α Foxo1, β-catenin, BMP-2, SP7 c-Fms

Regulation of HSCs function such as maintenance, self-renewal, reconstitution of hematopoiesis Inhibition of osteogenic differentiation, proliferation precursor of MSC Induction or inhibition of osteoblastic differentiation Positive or negative regulator of osteoclast development

Refs. 1,6,17–19,21

Refs. 1,23,25 Refs. 11–13 Refs. 3,12,15,16

HSC, hematopoietic stem cell; MSC, mesenchymal stem cell; PTH, parathyroid hormone; BMP-2, morphogenetic protein 2; Foxo-1, Forkhead box transcription factor O1; HIF-1α, hypoxia-inducible factor 1 α; Runx2, runt related transcription factor 2; NICD, intracellular domain of Notch.

MSC through increase in Notch1 protein by hypoxiainducible factor 1α.25 So, we can conclude that the Notch signaling pathway not only inhibits MSC differentiation, but will also enhance their proliferation. Table 1 shows cross-talk between components of Notch signaling pathway and BM components. Notch signaling pathway in BM is responsible for a separate role in each of the niche components such as MSCs, HSCs, osteoblasts, and osteoclasts. Notch regulates BM proliferation, differentiation, development, and maintenance through interaction with target genes of each of the BM components (Table 1).

Notch signaling in stem cell niche Notch signaling pathway plays a major role in regulating and controlling the key features of BM stem cells such as self-renewal, quiescence, and apoptosis. Notch ligands are the main components of the stem cell niche, boosting and maintaining stem cells by activating Notch receptors expressed by stem cells.1,5,17 Concurrent increase in the expression of Notch Jagged-1 ligand by endosteal cells and activation of osteoblasts by PTH in the stem cell niche, leads to an increased number and self-renewal of stem cells.17,21 Following BM myeloablation, endothelial cells regenerate the damage by expressing Notch ligands,27 suggesting the critical role of this signaling pathway in regulating the self-renewal of stem cells in the niche. The important role of Notch signaling pathway in quiescence regulation of stem cells has been studied. However, the role of Notch in regulating quiescence in HSC is different from its role in other stem cells.28–30 Evidences have shown that unlike the incremental role of Notch signaling in quiescence regulation of neural and muscle stem cells, it is not necessary for maintaining the quiescence of HSC.28 In addition to its role in maintaining the quiescence of stem cells, Hes-1 oscillation by Notch in neural stem cells causes these cells to quit the quiescent state.29 Notch signaling has also been evaluated in

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satellite cells (SCs), which are stem cells in skeletal muscles. Notch3 and downstream targets of Notchlike Hes-1 and Hey1 (Hairy/enhancer-of-split related with YRPW motif protein 1) have been found to be highly expressed in quiescent SCs. Therefore, Notch signaling is essential to maintain SCs quiescence in skeletal muscle stem cells.30 In this regard, nervous system plays an important role in migration of stem and progenitor cells, so that norepinephrine signaling controls the mobilization of these cells. Thus, the injection of β-2 adrenergic agonist will lead to increased mobilization of stem and progenitor cells to niche.31 The role of Notch during development of the central nervous system is also interesting to note. Notch is responsible for maintenance of neural progenitor cells. Therefore, reduced Notch activity is in line with a decrease in neural progenitors and increased neuronal differentiation.32 Given the above facts, it can be stated that Notch signaling may play a significant role in quiescence regulation of stem cells. However, the role of this pathway is not so prominent in maintenance of HSC quiescence. Notch signaling also plays an important role in apoptosis. Cross-talk between tumor necrosis factor α (TNFα) and Notch signaling controls endothelial cell apoptosis.33 TNFα is a cytokine found in considerable quantities in many tumors.34 In endothelial cells, TNFα causes up-regulation and down-regulation of Notch2 mRNA and Notch4 mRNA, respectively.33 Research has shown that survivin is an anti-apoptotic factor in the cells.35 Up-regulation of Notch2 molecule causes reduced levels of survivin in the cells, sensitizing the susceptible cells to apoptosis. Such a reaction between Notch2 molecule and survivin is consistent with reduced Notch activity by TNFα signaling. Thus, inhibition of Notch signaling by TNFα inhibits endothelial cell apoptosis.33 Chadwick et al. 36 also reported that sustained activation of Notch signaling pathway by aberrant expression of Notch 1 intracellular domain (N1ICD) through up-regulation of P21

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and Bcl2L1 can induce apoptosis in human CD34+ hematopoietic progenitor cells. Therefore, increased or decreased activity of Notch signaling pathway plays an important role in apoptosis regulation in stem cells. Notch also interacts with other apoptotic pathways during apoptosis. Notch pathway and apoptotic nuclear factor-kappa B (NF-kB) pathway have been introduced as important regulators of apoptosis, so that Notch1 inactivation results in apoptosis induction through NF-kB inactivation. Thus, it can be stated that Notch1 has an inhibitory function during apoptosis.37 Interaction between miRNA-206 and 3′ -untranslated region of Notch3 molecule leads to overexpression of microRNA (miRNA), decreased expression of Notch3 and blocking its anti-apoptotic activity, and finally apoptotic cell death.38 Endothelial cells are present in the BM vascular niche, and are involved in HSC maintenance, proliferation, and differentiation by providing a niche for HSC.39 Vascular cell-adhesion molecule-1 (VCAM-1) is expressed by endothelial cells. In addition to regulation of megakaryocyte maturation and platelet production, VCAM-1 plays an important role in homing of stem cells in the BM during cross-talk between HSCs and endothelial cells.40 BM endothelial cells secrete soluble factors such as PTEN (Phosphatase and tensin homolog), and are involved in regulating the self-renewal of HSCs.41 Mir-132 enhances the function of endothelial cells via up-regulating PTEN activity.42 In addition to the above-mentioned roles, endothelial cells play an important role in malignant niche. Secretion of cytokines and proangiogenic factors such as vascular endothelial growth factor (VEGF) and initiation of endothelial cell growth by tumor cells cause stimulation, chemotaxis, and binding of endothelial cells to endothelium. This process results in physiological regeneration and repairing of vessels in the tumor.43 Endothelial cell functions to augment the survival of leukemic stem cells including acute lymphoblastic leukemia (ALL) cells by modulating bcl-2 anti-apoptotic protein.41 The role of Notch signaling pathway in endothelial progenitor cell biology has also been studied. Notch signaling plays an important role in the function and kinetics of the BM-derived endothelial progenitor cells.44 In other words, maintenance, proliferation, and differentiation of endothelial progenitor cells and their role in vascular regeneration because of the Notch receptor–ligand interaction between these cells and the BM are regulated.45 In addition, the role of Notch signaling and endothelial progenitor cells in tumor angiogenesis are parallel. Therefore, we suggest further studies on the Notch signaling pathway between endothelial progenitor cells and the BM niche. These may shed light on these cellular

Notch signaling in bone marrow niche

mechanisms and therapeutic significance of these cells in vascular regeneration.46 Endothelial cells stimulate Notch signaling to enhance long-term selfrenewal of HSCs by angiocrine expression of Notch ligands including Jagged1–2, DII1, and DII4. This process inhibits the excessive differentiation of hematopoietic progenitor cells.20 Considering the extensive functions of endothelial cells in tumor growth, they can be called as cellular vectors that selectively target the tumor and deliver cytotoxic genes with antitumor effects in cells.47

Notch in metastatic niche Metastatic niche is a microenvironment to support the growth of cancer cells extravasated in tissues other than their tissue of origin.48 In metastatic niche, certain signaling pathways are activated in stem cells, which play a significant role in development of cancer cells in that niche.49 The Notch ligands and receptors play an important role in providing proper conditions for bone metastatic niche during interaction with growth factors released by osteoblasts and osteoclasts.48 Transforming growth factor-β (TGFβ) is secreted by bone matrix through osteoclastic activity, which stimulates JAG-1 expression. The role of JAG-1 as a Notch ligand is triggering sustained proliferation of metastatic cells and subsequent breakdown of bone tissue.48,50 Connective tissue growth factor functions as a target for TGFβ, and is responsible for angiogenesis and invasion during metastasis.50 Notch signaling pathway activation mediated by JAG associated with osteoblasts in metastatic niche is resulted from interleukin-6 (IL-6) secretion as a pro-proliferative cytokine during BM metastasis and tumor proliferation induction.48,50 The role of Jagged-1 ligand of Notch molecule in metastasis is so important that its overexpression will significantly increase tumor growth in damaged areas of bone.50 In other words, it can be stated that Jagged-1 is responsible for osteolytic bone metastasis, and TGFβJagged1-Notch-IL-6 interaction is a signaling network involved in development of bone metastasis. Tenascin C is another important molecule in metastatic niche for the cells involved in tumor initiation. This molecule supports survival of metastasis initiating cells by increasing the response of these cells to Notch signaling pathway in metastatic niche.51 Mechanisms of cancer metastasis cooperate or intervene with signaling pathways required for each stage of metastasis, and study of these mechanisms may result in therapeutic approaches.5 Patel et al. 52 studied the reaction between Notch–Jagged and claimed that it plays a crucial role in the engagement catalyst of cancer cells in addition to modulation of cell–cell connections. Cancer cells exploit the Notch–Jagged reaction in activation of osteoclasts

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originating from hematopoietic lineage and osteoblasts derived from MSCs. This mechanism accelerates and enhances the growth and invasion of cancer cells in the bone, eventually breaking down the bone tissue.52 Notch signaling pathway is important during angiogenesis, and its activation has been shown during specific stages in tumor angiogenesis.53 Notch signaling affects angiogenesis directly or indirectly through receptors for VEGF.54 VEGF, which is secreted in hypoxic conditions, has been introduced as the best angiogenic stimulus.55 The two types of endothelial cells required for angiogenesis sprouting have been entitled ‘tip’ cell and ‘stalk’ cell.54 During angiogenesis regulation stages, endothelial tip cells increase expressing DII4 and decrease Notch activity in response to a stimulatory gradient.55 The response of endothelial stalk cells to such Notch signaling is exerted via down-regulation of VEGF receptors such as VEGFR-2 and VEGF-3 to inhibit extra tube formation during angiogenesis process.54,55 Therefore, Notch plays an important role in angiogenesis regulation by regulating the signaling between VEGF and DII4 receptors. In one study, it was found that co-culture of breast cancer cells and fibroblasts leads to increased expression of chemokine (C–C motif ) ligand 2 (CCL2). This chemokine will induce the expression of Notch1 through increased self-renewal of cancer stem cells (CSCs). In other words, the absence of CCL2 regulates Notch1 via inhibition of tumorigenesis and expression of Notch1.56 Up-regulation of Notch2 in breast cancer is linked to increased survival, and blocking the expression of Notch3 is involved in reducing the invasiveness of cancer cells.57 Besides, the individual function of Notch ligands and receptors, interaction of cytokines with this signaling pathway plays a role in maintenance of carcinoma. IL-6 will increase self-renewal and hypoxic survival in breast carcinoma cells by regulation of Notch signaling.58 It has also been found that TGFβ1 cause increased bone metastasis by increasing the expression of Notch3 and Hes-1.57 Notch receptors also play critical roles during angiogenesis, so that the signaling regulation function of VEGF and DII4 receptors is prominent in angiogenesis.54,55 In addition to involvement of Notch receptors in metastasis, activation of its signaling pathway by Jagged-1 ligand causes osteolytic bone metastasis in breast cancer via regulation of TGFβ-SMAD signaling. As a result, Jagged-1 is known as an important clinical factor in breast cancer metastasis to bone.59 In completion of the above findings, it can be concluded that manipulation of Notch signaling pathway would be a supplementary and complementary therapeutic approach. This pathway will be

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promising for researchers in further studies on the role of this signaling pathway in cancer treatment because of targeting cancer metastasis.5

Notch in leukemic niche In addition to the role of Notch in controlling cell function in normal BM niche, aberrant expression of this signaling pathway can result in various neoplasias including hematological malignancies.3,60 In hematological malignancies, the role of Notch in disease progress includes apoptosis inhibition and induction of unchecked cancer cell proliferation. Moreover, many studies and clinical evidences have indicated tumor suppressor and/or oncogenic role of Notch signaling pathway in solid and hematological malignancies.5 Besides hematological malignancies, alteration of this signaling pathway has been reported in human breast tumors, melanoma progression, and medulloblastoma.60 Disruption of Notch signaling pathway has been found in myeloma.61 The role of Notch during progression and development of multiple myeloma (MM) is induced by aberrant expression of Notch ligands and receptors in various stages of the disease.61,62 Sustained expression of Notch1–3 and Jagged-1–2 ligands by malignant MM cells and expression of Dll and Jagged ligands by BM stromal cells are two distinct mechanisms in the activation of Notch signaling pathway in MM cells.63,64 Cross-talk between Notch ligands including Jagged-2 and BM stroma cells such as MRC5 fibroblasts play significant roles in the activation of Notch in MM cells.64 In this regard, Jagged-2 can activate Notch signaling in MCR5 fibroblasts by increased production of IL-6, VEGF, and insulin-like growth factor-1, which are essential inducers of malignant plasma cells in BM niche.65 Skeletrophin is an ubiquitin ligand aberrantly expressed in MM cells, resulting in dysregulation of Jagged-2 ligand and subsequent activation of Notch in resulting malignant stromal cells. The latter activation causes increased progression of disease by accelerating the growth and number of malignant MM stem cells.63,64 Contact between MM cells and BM stromal cells causes increased clonogenic growth and self-renewal of malignant CD138+ cells in patients following Dll1 expression in BM stromal cells.64 Therefore, Notch plays an important role in the stability of malignant plasma cells in BM niche through dysregulation of its components. It should be expressed both in MM and BM stromal cells to play its role.63,64 Dysregulation of Notch signaling pathway has also been observed in T-cell ALL (T-ALL).66 Mutations are another factor involving Notch signaling pathway in hematological neoplasias. t(7;9) chromosomal translocation causing N1ICD expression in T-cell

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Table 2 Dysregulation of Notch signaling in different cancer and metastasis disease

Tumor type

Involved notch component

T-ALL

Notch1–3

T-cell lymphoblastic leukemia/ lymphomas (T-LLs) B-CLL

Notch1

AML MM

Notch1–2, Jag1–2 Notch1, Jag1 Notch1–2, Jag1–2

Pancreatic cancer

Notch1–2, Delta-like 4

Breast cancer

Notch1, Notch3, Delta-like 1, Jag1

Prostate

Delta-like 1, Notch1, Jag1

Non-small cell lung carcinoma Glioblastoma

Notch1, Notch3 Notch1–2

Target gene

Receptor/ ligand as

Reference

GSIs, antiNOTCH1 inhibitory antibodies, glucocorticoids strong synergy between glucocorticoids and GSIs

—

Refs. 66,69

—

Refs. 70

Oncogenic

GSIs

—

Refs. 67,71,72

Oncogenic Oncogenic

Notch agonist peptide GSIs

— —

Refs. 73,74 Refs. 5,71,75

Oncogenic

Inhibition of Notch expression by sulforaphane, quercetin, curcumin, isoflavone GSIs of Notch such as MK-0752 (Merck) in combination with tamoxifen or letrozole

miR-34, miR-200 miR-21

Refs. 72,76–78

miR-200c, miR34a

Refs. 72,76,79–81

Genistein by inhibition the activation of the NF-kB pathway by Notch signaling —

miR-34a, miR-1

Refs. 76,77,82–84

miR-1, miR-200b

Refs. 68,76

Curcumin by inhibition cell growth and induction apoptosis by inactivation of Notch pathway

miR-34a

Refs. 72,76,77,85

c-Myc, A1/Bfl1 c-Myc and Hes-1

Oncogenic

c-IAP2, XIAP Hes-1 Hes-1, NF-kB, c-Myc NF-kB, MMP-9, and VEGF Hes-1/5, Ras, PKB/ Akt, Numb Hes-1, MMP-9, VEGF

Oncogenic

EGF-R, ADAM17 EGF-R

Notch-related drug therapy

miRNA in crosstalk with Notch correlated to drug resistance

Oncogenic

Tumor suppressive

Oncogenic

Oncogenic

T-ALL, T-cell acute lymphoblastic leukemia; GSIs, gamma-secretase inhibitors; MM, multiple myeloma; AML, acute myeloid leukemia; VEGF, vascular endothelial growth factor; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B-cells; MMP-9, matrix metalloproteinase 9; EGF-R, epidermal growth factor receptor; Hes-1, hairy and enhancer of split-1; ADAM-17, a disintegrin and metalloproteinase 17; B-CLL, B-cell chronic lymphocytic leukemia; c-IAP2, cellular inhibitor of apoptosis protein 2; XIAP, X-linked inhibitor of apoptosis protein.

receptor-β indicates the role of Notch1 in most of the T-ALL patients.3 Notch1 mutations in T-ALL constitute activated alleles causing abnormally high levels of Notch signaling. Exons 26 and 27 are the most frequent mutation hotspots in Notch1 molecule, another one being the second PEST ( proline, glutamic acid, serine, and threonine) of Notch1 molecule.66 Notch signaling pathway aberration has also been seen in acute myeloid leukemia, which is associated with Jagged-1 and Notch1 overexpression.5 B-cell chronic lymphocytic leukemia (B-CLL) is among the most common lymphoproliferative disorders. In the B-CLL, dysregulation of Notch signaling pathway is indicated by continuous expression of Notch receptors 1–2 and the related ligands of Jagged-1 and Jagged2.67,68 Table 2 shows the relationship between various cancer types and metastatic diseases with dysregulation of components of Notch signaling pathway. As the table shows, the Notch signaling is deregulated

during cancers and malignancies. Notch pathway components, including oncogene or tumor suppressor, in these malignancies implicated in the pathogenesis via interaction with the target genes. In addition, interacting miRNA and Notch molecules are also responsible for resistance to therapy. However, better understanding of the components involved in the Notch in various malignancies and using underutilized treatment strategies such as GSI, antibody against the involved Notch components, and inhibiting their expression may be considered as important points during treatment (Table 2).

Notch and miRNA The miRNAs are small single-stranded RNA molecules regulating gene expression by inhibition of translation or by mRNA degradation.7 Research has demonstrated the relationship between miRNA and Notch signaling pathway during regulation of bone

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Table 3

Interaction of miRNA and Notch signaling in normal and neoplasia regulation

Regulation

Notch signaling

miRNA

Function

References

Normal regulation

Notch1–2, Jag1 Notch3 Notch

Neoplasia regulation

Notch1

miR-34c miR-150 miR-181 miR-326 miR-144 miR-34a miR-146a miR-19 miR-34 miR-199b-5p

Inhibition of osteoclastogenesis Adverse effect on T-cell development NK cell development, inhibitory role in B-cell differentiation maintenance of GSCs (‘stemness’, proliferation) Inhibition of colorectal cancer Translational inhibition in choriocarcinoma cells Inhibition of glioma development Induction of leukemogenesis Pancreatic CSC self-renewal Negative regulator of Notch in osteosarcoma

Refs. 7 Refs. 89 Refs. 86,87 Refs. 88 Refs. 91 Refs. 92 Refs. 93 Refs. 94 Refs. 90 Refs. 90

Notch1, Notch2 Hes-1

and hematopoietic cell homeostasis as well as in various malignancies. In the process of bone homeostasis, miR-34c regulates osteoclasts by targeting the components of Notch signaling pathway.7,86–91 In this regard, miR-34c inhibits osteoclastogenesis through the inhibition of Jag1 and Notch1–2.7 In addition, miRNA and Notch signaling have been found to play an important role in the expansion of natural killer cells (NK cells). In this regard, miR181 promotes human NK cell development by enhancing the activity of Notch.86 Besides the stimulatory role of miR-181 in Notch activity, its inhibitory role has been demonstrated during B-cell development.87 Notch is a target molecule of miR-326, which is involved in maintenance of glioma stem cell proliferation and stemness.88 Forced expression of miR-150 adversely affects the proliferation of T-cell lines by reducing Notch3 expression during differentiation of T-cells.89 Due to the involvement of miRNA in apoptosis and cell proliferation during development of human malignancies, miRNAs are deemed to be involved in development of cancer along with aberrant activation of Notch signaling pathway. In medulloblastoma, miR199b-5p acts as an inhibitory regulator of Notch signaling through inhibition of Hes-1.90 DCAMKL-1 is up-regulated microtubule kinase that plays an important role in pancreatic and colorectal cancers. In his study, Sureban reported that DCAMKL-1 inhibits colorectal cancer by increasing miR-144 through down-regulation of Notch-1 molecule.91 The miR34a is a different miRNA that inhibits cancer cells through interaction with Notch signaling. MiR-34a in choriocarcinoma cells inhibits translation through inhibition of Notch-1 expression.92 Besides the role of Notch-1 in colorectal cancer, Mei et al. showed involvement of Notch molecule in glioblastoma, but Notch-1 is inhibited by miR-146a in this type of cancer.93 miR-19 is among miRNAs causing leukemogenesis in Notch-1-induced T-ALL.94 miRNA function in differentiation regulation of osteoblasts and osteoclasts is prominent besides its role in Notch signaling pathway.95–97 In particular, miR-637 and miR-23a-27a-24-2 related cluster will

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inhibit differentiation of osteoblasts.95 Differentiation of osteoblasts is concomitant with reduced expression of miR-206.96 The inhibition of differentiation of osteoclasts has been declared by miRNAs such as miR-146 and miR-29b.97,98 Finally, miRNA molecules and Notch signaling are involved in proliferation, development, and general homeostasis of resident cells in normal BM niche through their interactions. This interaction is impaired in malignant BM niche, i.e. their role in the regulation of neoplastic niche is out of control. It is assumed that changing expression of miR molecules and subsequent Notch signaling deregulation increases the likelihood of progress of malignancies in the BM. Detection of important miRNAs in BM microenvironment requires further studies to compare the miRNAs expressed in normal and neoplastic niches in order to suggest appropriate treatment targets. Table 3 shows a diagram of the cross-talk between miRNA molecules and Notch signaling pathway components.

Therapy and drug resistance of Notch in niche Aberrant expression or dysregulation of Notch signaling pathway components has been reported in a variety of malignancies. Therefore, this important cell signaling pathway has been increasingly considered in the treatment of various cancer types and metastasis.74 Inhibiting Notch receptors and ligands by different therapeutic strategies such as GSIs, monoclonal antibodies, glucocorticoids, and natural agents has been discussed in the treatment of malignancies.74 Since GS plays an important role in Notch signaling, it can be considered as a therapeutic target.99 In this regard, GSIs reduce tumor growth and induce apoptosis in several human cancers as anti-tumor agents. However, non-specificity of GSIs and cytotoxicity in some tissues, particularly the gastrointestinal tract are factors restricting the use of these therapeutic agents.74 Development of antibodies that selectively inhibit Notch receptors and gut toxicity may be another therapeutic approach. However, the effects of antibodies in treatment, like that of T-ALL, have not been reported to be as strong as GSIs.72 The use of GSIs alone showed limited efficacy in the treatment

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of leukemic diseases like T-ALL. In this regard, compensatory outcomes have been achieved in combined treatments. Combined treatment of GSI with other inhibitors such as cyclin-dependent kinase inhibitors and inhibitors of PI3K-AKT-mTOR pathway and glucocorticoids has resulted in better anti-leukemic effects.66 Natural agents are compounds in fruits and vegetables as well as flavoring agent in foods, which play an important role in malignancies such as pancreatic cancer. They inhibit growth and apoptosis induction by inactivating Notch pathway.74 Besides therapeutic roles of Notch, laboratory evidences suggest it as an anti-cancer drug-resistant entity. CSCs and epithelial–mesenchymal transition (EMT) phenotype are drug-resistant factors. Elimination of CSCs and EMT-type cells by Notch will overcome the drug resistance of cancer cells.73 Cross-talk between Notch and miRNA is also effective in overcoming the drug resistance phenotype of cancer cells. miR-34, miR-1, miR-21, and miR-200 are miRNAs involved in reducing drug resistance of cancer cells by regulating Notch signaling.73

Discussion Notch signaling pathway is a signaling pathway involved in cellular processes such as proliferation, differentiation, and apoptosis. The relationship between Notch signaling pathway with miRNA and stem cells has also been reported in many studies. In addition to regulating cellular functions, aberrant expression of this signaling pathway has been observed in a number of cancers and metastatic diseases. Aberrant expression of miRNA molecules and disruption of Notch signaling pathway are important factors contributing to malignancy. The genes involved in Notch signaling pathway are the targets for miRNAs implicated in malignancy. For example, three miRNA molecules associated with Notch signaling have been mentioned to be down-regulated in glioma, including miR-128, miR-218, and miR-26a.100 Uncontrolled expression of DLL4 in endothelial cells will lead to excessive sprouting. Given the role of miR-30 in angiogenesis, it can be assumed that DLL4 enables the critical role of angiogenesis in cancer development as a target for miR-30.101 Therefore, this important cell signaling pathway has been increasingly considered in the treatment of a variety of cancer types and metastasis. In conclusion, future studies on a variety of cancers and apoptosis can aim at Notch signaling pathway as a safe and effective therapeutic target.

Disclaimer statements Contributors N.S., K.J., and F.R. conceived the manuscript and revised it; N.S., S.A., Me.Sh.B., Ma.Sh.B., and M.S.

Notch signaling in bone marrow niche

wrote the manuscript. S.A., S.S., M.G., and F.S. prepares the figure and tables. Funding None. Conflicts of interest None. Ethics approval None.

Acknowledgements We wish to thank all our colleagues in Shafa Hospital and Allied Health Sciences School, Ahvaz Jundishapur University of Medical Sciences.

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