The tissue inhibitor of metalloproteinases 1 increases the clonogenic efficiency of human hematopoietic progenitor cells through CD63/PI3K/Akt signaling

Rossi, Lara; Forte, Dorian; Migliardi, Giorgia; Salvestrini, Valentina; Buzzi, Marina; Ricciardi, Maria Rosaria; Licchetta, Roberto; Tafuri, Agostino; Bicciato, Silvio; Cavo, Michèle; Catani, Lucia; Lemoli, Roberto M.; Curti, Antonio

doi:10.1016/j.exphem.2015.07.003

Cited by 24 publications

(29 citation statements)

References 54 publications

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“…In our previous work [22], we found that TIMP-1 increases the clonogenic efficiency of normal HSPCs isolated from umbilical CB units. Thus, we studied the effects of increasing concentration of TIMP-1 (ranging between 10–300 ng/ml) on the clonogenic output of 14 primary AML at diagnosis.…”

Section: Resultsmentioning

confidence: 97%

“…In normal hematopoiesis, TIMP-1 regulates the survival and proliferation of different cell types [15, 22]. However, its role in AML BM microenvironment is not yet clear.…”

Section: Resultsmentioning

confidence: 99%

“…At the functional level, TIMP-1 exerts pleiotropic effects in the BM microenvironment, such as the regulation of cellular proliferation, apoptosis and differentiation [19–21]. In particular, we previously found that TIMP-1 regulates the function of HSPCs promoting clonogenic efficiency and survival of normal CD34 + cells via the activation of the CD63/PI3K/pAkt signaling pathway, suggesting that TIMP-1 may be a key player in the network of pro-inflammatory factors modulating HSPC functions [22]. Similarly, in solid tumors, TIMP-1 improves the metastatic potential of cancer cells [23].…”

Section: Introductionmentioning

confidence: 99%

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The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes survival and migration of acute myeloid leukemia cells through CD63/PI3K/Akt/p21 signaling

et al. 2016

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We and others have shown that the Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), a member of the inflammatory network exerting pleiotropic effects in the bone marrow (BM) microenvironment, regulates the survival and proliferation of different cell types, including normal hematopoietic progenitor cells. Moreover, TIMP-1 has been shown to be involved in cancer progression. However, its role in leukemic microenvironment has not been addressed. Here, we investigated the activity of TIMP-1 on Acute Myelogenous Leukemia (AML) cell functions. First, we found that TIMP-1 levels were increased in the BM plasma of AML patients at diagnosis. In vitro, recombinant human (rh)TIMP-1 promoted the survival and cell cycle S-phase entry of AML cells. These kinetic effects were related to the downregulation of cyclin-dependent kinase inhibitor p21. rhTIMP-1 increases CXCL12-driven migration of leukemic cells through PI3K signaling. Interestingly, activation of CD63 receptor was required for TIMP-1's cytokine/chemokine activity. Of note, rhTIMP-1 stimulation modulated mRNA expression of Hypoxia Inducible Factor (HIF)-1α, downstream of PI3K/Akt activation. We then co-cultured AML cells with normal or leukemic mesenchymal stromal cells (MSCs) to investigate the interaction of TIMP-1 with cellular component(s) of BM microenvironment. Our results showed that the proliferation and migration of leukemic cells were greatly enhanced by rhTIMP-1 in presence of AML-MSCs as compared to normal MSCs. Thus, we demonstrated that TIMP-1 modulates leukemic blasts survival, migration and function via CD63/PI3K/Akt/p21 signaling. As a “bad actor” in a “bad soil”, we propose TIMP-1 as a potential novel therapeutic target in leukemic BM microenvironment.

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Section: Resultsmentioning

confidence: 97%

“…In normal hematopoiesis, TIMP-1 regulates the survival and proliferation of different cell types [15, 22]. However, its role in AML BM microenvironment is not yet clear.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes survival and migration of acute myeloid leukemia cells through CD63/PI3K/Akt/p21 signaling

et al. 2016

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“…Mononuclear cells (MNCs) were separated from MF and CB samples by stratification on Lympholyte-H 1.077 g/cm 3 gradient (Gibco-Invitrogen, Milan, Italy), followed by red blood cell lysis for 15 min at 4°C. MNCs were then processed on magnetic columns for CD34 + cell isolation (mean purity 94% ± 5%) (MACS CD34 Isolation kit; Miltenyi Biotech, Bologna, Italy), as previously described [37]. …”

Section: Methodsmentioning

confidence: 99%

“…TIMP-1, through receptor (CD63) binding, promotes cell survival, differentiation and migration; also, TIMP-1 displays cytokine-like features in the HSPC compartment [33–35]. It was initially found to enhance the proliferation of erythroid cells [36]; also, we recently demonstrated that TIMP-1 increases the clonogenic efficiency of normal CB-derived progenitor cells [37]. Finally, extracellular nucleotides, mainly ATP, are important mediators in inflammation and modulation of cell proliferation, migration and death, including AL CD34 + stem/progenitor cells [24, 37–41].…”

Section: Introductionmentioning

confidence: 99%

Crucial factors of the inflammatory microenvironment (IL-1β/TNF-α/TIMP-1) promote the maintenance of the malignant hemopoietic clone of myelofibrosis: an in vitro study

et al. 2016

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Along with molecular abnormalities (mutations in JAK2, Calreticulin (CALR) and MPL genes), chronic inflammation is the major hallmark of Myelofibrosis (MF). Here, we investigated the in vitro effects of crucial factors of the inflammatory microenvironment (Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α, Tissue Inhibitor of Metalloproteinases (TIMP)-1 and ATP) on the functional behaviour of MF-derived circulating CD34+ cells.We found that, regardless mutation status, IL-1β or TNF-α increases the survival of MF-derived CD34+ cells. In addition, along with stimulation of cell cycle progression to the S-phase, IL-1β or TNF-α ± TIMP-1 significantly stimulate(s) the in vitro clonogenic ability of CD34+ cells from JAK2V617 mutated patients. Whereas in the JAK2V617F mutated group, the addition of IL-1β or TNF-α + TIMP-1 decreased the erythroid compartment of the CALR mutated patients. Megakaryocyte progenitors were stimulated by IL-1β (JAK2V617F mutated patients only) and inhibited by TNF-α. IL-1β + TNF-α + C-X-C motif chemokine 12 (CXCL12) ± TIMP-1 highly stimulates the in vitro migration of MF-derived CD34+ cells. Interestingly, after migration toward IL-1β + TNF-α + CXCL12 ± TIMP-1, CD34+ cells from JAK2V617F mutated patients show increased clonogenic ability.Here we demonstrate that the interplay of these inflammatory factors promotes and selects the circulating MF-derived CD34+ cells with higher proliferative activity, clonogenic potential and migration ability. Targeting these micro-environmental interactions may be a clinically relevant approach.

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Revisiting the Role of CD63 as Pro‐Tumorigenic or Anti‐Tumorigenic Tetraspanin in Cancers and its Theragnostic Implications

2023

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Cluster of differentiation antigen 63 (CD63) belongs to a superfamily of proteins, usually defined as tetraspanins which are known to transverse the bilayer membranes four times. The expression of CD63 has been shown to get altered in several cancers, where it has been demonstrated to act as both a tumor promoter and tumor suppressor. The present review describes the mechanism of how CD63 promotes tumor formation in certain cancer types while inhibiting in some other specific cancers. Glycosylation, a post-translational process plays a significant role in regulating the expression and function of these membrane proteins. Being a crucial exosomal flag protein, CD63 has been found to get involved in endosomal cargo sorting as well as the production of extracellular vesicles. Increased expression of exosomal CD63 derived from advanced tumors has demonstrated its role in promoting metastasis. CD63 also regulates the characteristic and function of stem cells on which they get expressed. This particular tetraspanin has been discovered to participate in gene fusion to perform distinctive roles in certain specific cancer types like breast cancer and pigmented epithelioid melanocytoma. Furthermore, this review mentions twelve different microRNAs obtained from miRDB that might target CD63. A few theragnostic uses of this membrane protein are also discussed. Thereby, the review indicates that further studies on CD63 might prove it to be an effective therapeutic target in different cancers in the coming future.

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The tissue inhibitor of metalloproteinases 1 increases the clonogenic efficiency of human hematopoietic progenitor cells through CD63/PI3K/Akt signaling

Cited by 24 publications

References 54 publications

The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes survival and migration of acute myeloid leukemia cells through CD63/PI3K/Akt/p21 signaling

The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes survival and migration of acute myeloid leukemia cells through CD63/PI3K/Akt/p21 signaling

Crucial factors of the inflammatory microenvironment (IL-1β/TNF-α/TIMP-1) promote the maintenance of the malignant hemopoietic clone of myelofibrosis: an in vitro study

Revisiting the Role of CD63 as Pro‐Tumorigenic or Anti‐Tumorigenic Tetraspanin in Cancers and its Theragnostic Implications

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