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Article: Targeting hypoxia signaling pathways in angiogenesis.

Monaci, Sara / Coppola, Federica / Filippi, Irene / Falsini, Alessandro / Carraro, Fabio / Naldini, Antonella

2024 Volume 15, Page(s) 1408750

Abstract: ... Oxygen ( ... ...

Abstract	Oxygen (O
Language	English
Publishing date	2024-04-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2024.1408750
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Interplay between Hypoxia and Extracellular Vesicles in Cancer and Inflammation.

Venturella, Marta / Criscuoli, Mattia / Carraro, Fabio / Naldini, Antonella / Zocco, Davide

Biology

2021 Volume 10, Issue 7

Abstract: Hypoxia is a severe stress condition often observed in cancer and chronically inflamed cells and tissues. Extracellular vesicles play pivotal roles in these pathological processes and carry biomolecules that can be detected in many biofluids and may be ... ...

Abstract	Hypoxia is a severe stress condition often observed in cancer and chronically inflamed cells and tissues. Extracellular vesicles play pivotal roles in these pathological processes and carry biomolecules that can be detected in many biofluids and may be exploited for diagnostic purposes. Several studies report the effects of hypoxia on extracellular vesicles' release, molecular content, and biological functions in disease. This review summarizes the most recent findings in this field, highlighting the areas that warrant further investigation.
Language	English
Publishing date	2021-06-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology10070606
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Article: Role of the Hedgehog Pathway and CAXII in Controlling Melanoma Cell Migration and Invasion in Hypoxia.

Giuntini, Gaia / Coppola, Federica / Falsini, Alessandro / Filippi, Irene / Monaci, Sara / Naldini, Antonella / Carraro, Fabio

Cancers

2022 Volume 14, Issue 19

Abstract: Background: Malignant melanoma is the leading cause of death among skin cancer patients due to its tendency to metastasize. Alterations at the molecular level are often evident, which is why melanoma biology has garnered increasing interest. The ... ...

Abstract	Background: Malignant melanoma is the leading cause of death among skin cancer patients due to its tendency to metastasize. Alterations at the molecular level are often evident, which is why melanoma biology has garnered increasing interest. The hedgehog (Hh) pathway, which is essential for embryonic development, is aberrantly re-activated in melanoma and may represent a promising therapeutic target. In addition, carbonic anhydrase XII (CAXII) represents a poor prognostic target for hypoxic tumors, such as melanoma, and is involved in cell migration. Thus, we decided to investigate whether and how the Hh pathway and CAXII may control melanoma cell migration and invasiveness. Methods: The migratory and invasive capabilities of SK-MEL-28 and A375 cell lines, either un-transfected or transiently transfected with Smoothened (SMO), GLI1, or CAXII siRNA, were studied under normoxic or hypoxic conditions. Results: For the first time, we showed that SMO and GLI1 silencing resulted in the downregulation of CAXII expression in both moderately and highly invasive melanoma cells under hypoxia. The Hh pathway as well as CAXII inhibition by siRNA resulted in impaired malignant melanoma migration and invasion. Conclusion: Our results suggest that CAXII and the Hh pathway are relevant in melanoma invasion and may be novel and promising therapeutical targets for melanoma clinical management.
Language	English
Publishing date	2022-09-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14194776
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Article ; Online: CA-IX-Expressing Small Extracellular Vesicles (sEVs) Are Released by Melanoma Cells under Hypoxia and in the Blood of Advanced Melanoma Patients.

Venturella, Marta / Falsini, Alessandro / Coppola, Federica / Giuntini, Gaia / Carraro, Fabio / Zocco, Davide / Chiesi, Antonio / Naldini, Antonella

International journal of molecular sciences

2023 Volume 24, Issue 7

Abstract: Cutaneous melanoma is a highly aggressive skin cancer, with poor prognosis. The tumor microenvironment is characterized by areas of hypoxia. Carbonic anhydrase IX (CA-IX) is a marker of tumor hypoxia and its expression is regulated by hypoxia-inducible ... ...

Abstract	Cutaneous melanoma is a highly aggressive skin cancer, with poor prognosis. The tumor microenvironment is characterized by areas of hypoxia. Carbonic anhydrase IX (CA-IX) is a marker of tumor hypoxia and its expression is regulated by hypoxia-inducible factor-1 (HIF-1). CA-IX has been found to be highly expressed in invasive melanomas. In this study, we investigated the effects of hypoxia on the release of small extracellular vesicles (sEVs) in two melanoma in vitro models. We demonstrated that melanoma cells release sEVs under both normoxic and hypoxic conditions, but only hypoxia-induced sEVs express CA-IX mRNA and protein. Moreover, we optimized an ELISA assay to provide evidence for CA-IX protein expression on the membranes of the sEVs. These CA-IX-positive sEVs may be exploited as potential biomarkers for liquid biopsy.
MeSH term(s)	Humans ; Antigens, Neoplasm/metabolism ; Biomarkers, Tumor/metabolism ; Carbonic Anhydrase IX/genetics ; Carbonic Anhydrases/metabolism ; Hypoxia ; Melanoma/genetics ; Skin Neoplasms ; Tumor Microenvironment ; Melanoma, Cutaneous Malignant
Chemical Substances	Antigens, Neoplasm ; Biomarkers, Tumor ; Carbonic Anhydrase IX (EC 4.2.1.1) ; Carbonic Anhydrases (EC 4.2.1.1) ; CA9 protein, human (EC 4.2.1.1)
Language	English
Publishing date	2023-03-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24076122
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Article ; Online: SQSTM1/p62 inhibition impairs pro-survival signaling in hypoxic human dendritic cells.

Coppola, Federica / Monaci, Sara / Falsini, Alessandro / Aldinucci, Carlo / Filippi, Irene / Rossi, Daniela / Carraro, Fabio / Naldini, Antonella

Biochimica et biophysica acta. Molecular cell research

2023 Volume 1871, Issue 2, Page(s) 119625

Abstract: The sequestosome 1 (SQSTM1)/p62 is an adaptor protein which plays multiple roles in several cell functions, including cell survival and autophagy. Dendritic cells (DCs) are the most prominent antigen presenting cells and during their lifespan they are ... ...

Abstract	The sequestosome 1 (SQSTM1)/p62 is an adaptor protein which plays multiple roles in several cell functions, including cell survival and autophagy. Dendritic cells (DCs) are the most prominent antigen presenting cells and during their lifespan they are exposed to different oxygen tensions, including hypoxia. By using a siRNA approach we found out that p62 was implicated in the maintenance of Erk1/2 phosphorylation and preservation of hypoxic DC survival, as well as in the reduction of AMPK activation. Thus, p62 expression in DCs in hypoxic microenvironments, such as in the lymphoid organs, may extend their lifespan to ensure their functions.
MeSH term(s)	Humans ; Sequestosome-1 Protein/genetics ; Sequestosome-1 Protein/metabolism ; Signal Transduction/physiology ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Hypoxia ; Dendritic Cells/metabolism
Chemical Substances	Sequestosome-1 Protein ; Adaptor Proteins, Signal Transducing ; SQSTM1 protein, human
Language	English
Publishing date	2023-11-18
Publishing country	Netherlands
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamcr.2023.119625
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Article: Interplay between Hypoxia and Extracellular Vesicles in Cancer and Inflammation

Venturella, Marta / Criscuoli, Mattia / Carraro, Fabio / Naldini, Antonella / Zocco, Davide

Biology. 2021 June 30, v. 10, no. 7

2021

Abstract	Hypoxia is a severe stress condition often observed in cancer and chronically inflamed cells and tissues. Extracellular vesicles play pivotal roles in these pathological processes and carry biomolecules that can be detected in many biofluids and may be exploited for diagnostic purposes. Several studies report the effects of hypoxia on extracellular vesicles’ release, molecular content, and biological functions in disease. This review summarizes the most recent findings in this field, highlighting the areas that warrant further investigation.
Keywords	biochemical compounds ; hypoxia ; inflammation
Language	English
Dates of publication	2021-0630
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology10070606
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Article ; Online: Human colorectal cancer: upregulation of the adaptor protein Rai in TILs leads to cell dysfunction by sustaining GSK-3 activation and PD-1 expression.

Montecchi, Tommaso / Nannini, Giulia / De Tommaso, Domiziana / Cassioli, Chiara / Coppola, Federica / Ringressi, Maria Novella / Carraro, Fabio / Naldini, Antonella / Taddei, Antonio / Marotta, Giuseppe / Amedei, Amedeo / Baldari, Cosima T / Ulivieri, Cristina

Cancer immunology, immunotherapy : CII

2024 Volume 73, Issue 1, Page(s) 2

Abstract: Background: The immunosuppressive tumor microenvironment (TME) of colorectal cancer (CRC) is a major hurdle for immune checkpoint inhibitor-based therapies. Hence characterization of the signaling pathways driving T cell exhaustion within TME is a ... ...

Abstract	Background: The immunosuppressive tumor microenvironment (TME) of colorectal cancer (CRC) is a major hurdle for immune checkpoint inhibitor-based therapies. Hence characterization of the signaling pathways driving T cell exhaustion within TME is a critical need for the discovery of novel therapeutic targets and the development of effective therapies. We previously showed that (i) the adaptor protein Rai is a negative regulator of T cell receptor signaling and T helper 1 (Th1)/Th17 cell differentiation; and (ii) Rai deficiency is implicated in the hyperactive phenotype of T cells in autoimmune diseases. Methods: The expression level of Rai was measured by qRT-PCR in paired peripheral blood T cells and T cells infiltrating tumor tissue and the normal adjacent tissue in CRC patients. The impact of hypoxia-inducible factor (HIF)-1α on Rai expression was evaluated in T cells exposed to hypoxia and by performing chromatin immunoprecipitation assays and RNA interference assays. The mechanism by which upregulation of Rai in T cells promotes T cell exhaustion were evaluated by flow cytometric, qRT-PCR and western blot analyses. Results: We show that Rai is a novel HIF-1α-responsive gene that is upregulated in tumor infiltrating lymphocytes of CRC patients compared to patient-matched circulating T cells. Rai upregulation in T cells promoted Programmed cell Death protein (PD)-1 expression and impaired antigen-dependent degranulation of CD8 Conclusions: Our data identify Rai as a hitherto unknown regulator of the TME-induced exhausted phenotype of human T cells.
MeSH term(s)	Humans ; CD8-Positive T-Lymphocytes ; Colorectal Neoplasms/genetics ; Glycogen Synthase Kinase 3 ; Hypoxia ; Lymphocytes, Tumor-Infiltrating ; Programmed Cell Death 1 Receptor/genetics ; Tumor Microenvironment ; Up-Regulation
Chemical Substances	Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; Programmed Cell Death 1 Receptor ; PDCD1 protein, human ; PPP1R13L protein, human
Language	English
Publishing date	2024-01-04
Publishing country	Germany
Document type	Journal Article
ZDB-ID	195342-4
ISSN	1432-0851 ; 0340-7004
ISSN (online)	1432-0851
ISSN	0340-7004
DOI	10.1007/s00262-023-03614-0
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Article: Hedgehog Pathway Inhibition by Novel Small Molecules Impairs Melanoma Cell Migration and Invasion under Hypoxia.

Falsini, Alessandro / Giuntini, Gaia / Mori, Mattia / Ghirga, Francesca / Quaglio, Deborah / Cucinotta, Antonino / Coppola, Federica / Filippi, Irene / Naldini, Antonella / Botta, Bruno / Carraro, Fabio

Pharmaceuticals (Basel, Switzerland)

2024 Volume 17, Issue 2

Abstract: Melanoma is the principal cause of death in skin cancer due to its ability to invade and cause metastasis. Hypoxia, which characterises the tumour microenvironment (TME), plays an important role in melanoma development, as cancer cells can adapt and ... ...

Abstract	Melanoma is the principal cause of death in skin cancer due to its ability to invade and cause metastasis. Hypoxia, which characterises the tumour microenvironment (TME), plays an important role in melanoma development, as cancer cells can adapt and acquire a more aggressive phenotype. Carbonic anhydrases (CA) activity, involved in pH regulation, is related to melanoma cell migration and invasion. Furthermore, the Hedgehog (Hh) pathway, already known for its role in physiological processes, is a pivotal character in cancer cell growth and can represent a promising pharmacological target. In this study, we targeted Hh pathway components with cyclopamine, glabrescione B and C22 in order to observe their effect on carbonic anhydrase XII (CAXII) expression especially under hypoxia. We then performed a migration and invasion assay on two melanoma cell lines (SK-MEL-28 and A375) where Smoothened, the upstream protein involved in Hh regulation, and GLI1, the main transcription factor that determines Hh pathway activation, were chemically inhibited. Data suggest the existence of a relationship between CAXII, hypoxia and the Hedgehog pathway demonstrating that the chemical inhibition of the Hh pathway and CAXII reduction resulted in melanoma migration and invasion impairment especially under hypoxia. As in recent years drug resistance to small molecules has arisen, the development of new chemical compounds is crucial. The multitarget Hh inhibitor C22 proved to be effective without signs of cytotoxicity and, for this reason, it can represent a promising compound for future studies, with the aim to reach a better melanoma disease management.
Language	English
Publishing date	2024-02-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph17020227
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Article ; Online: Hypoxia Induces Autophagy in Human Dendritic Cells: Involvement of Class III PI3K/Vps34.

Monaci, Sara / Coppola, Federica / Rossi, Daniela / Giuntini, Gaia / Filippi, Irene / Marotta, Giuseppe / Sozzani, Silvano / Carraro, Fabio / Naldini, Antonella

Cells

2022 Volume 11, Issue 10

Abstract: Hypoxia is a component of both physiological and pathological conditions, including inflammation, solid tumors, and lymphoid tissues, where ... ...

Abstract	Hypoxia is a component of both physiological and pathological conditions, including inflammation, solid tumors, and lymphoid tissues, where O
MeSH term(s)	Autophagy/physiology ; Class III Phosphatidylinositol 3-Kinases/metabolism ; Dendritic Cells/metabolism ; Humans ; Hypoxia ; Signal Transduction
Chemical Substances	Class III Phosphatidylinositol 3-Kinases (EC 2.7.1.137)
Language	English
Publishing date	2022-05-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11101695
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Article: Inhibition of Melanoma Cell Migration and Invasion Targeting the Hypoxic Tumor Associated CAXII.

Giuntini, Gaia / Monaci, Sara / Cau, Ylenia / Mori, Mattia / Naldini, Antonella / Carraro, Fabio

Cancers

2020 Volume 12, Issue 10

Abstract: Background: Intratumoral hypoxia contributes to cancer progression and poor prognosis. Carbonic anhydrases IX (CAIX) and XII (CAXII) play pivotal roles in tumor cell adaptation and survival, as aberrant Hedgehog (Hh) pathway does. In malignant melanoma ... ...

Abstract	Background: Intratumoral hypoxia contributes to cancer progression and poor prognosis. Carbonic anhydrases IX (CAIX) and XII (CAXII) play pivotal roles in tumor cell adaptation and survival, as aberrant Hedgehog (Hh) pathway does. In malignant melanoma both features have been investigated for years, but they have not been correlated before and/or identified as a potential pharmacological target. Here, for the first time, we demonstrated that malignant melanoma cell motility was impaired by targeting CAXII via either CAs inhibitors or through the inhibition of the Hh pathway. Methods: We tested cell motility in three melanoma cell lines (WM-35, SK-MEL28, and A375), with different invasiveness capabilities. To this end we performed a scratch assay in the presence of the smoothened (SMO) antagonist cyclopamine (cyclo) or CAs inhibitors under normoxia or hypoxia. Then, we analyzed the invasiveness potential in the cell lines which were more affected by cyclo and CAs inhibitors (SK-MEL28 and A375). Western blot was employed to assess the expression of the hypoxia inducible factor 1α, CAXII, and FAK phosphorylation. Immunofluorescence staining was performed to verify the blockade of CAXII expression. Results: Hh inhibition reduced melanoma cell migration and CAXII expression under both normoxic and hypoxic conditions. Interestingly, basal CAXII expression was higher in the two more aggressive melanoma cell lines. Finally, a direct CAXII blockade impaired melanoma cell migration and invasion under hypoxia. This was associated with a decrease of FAK phosphorylation and metalloprotease activities. Conclusions: CAXII may be used as a target for melanoma treatment not only through its direct inhibition, but also through Hh blockade.
Language	English
Publishing date	2020-10-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12103018
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