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Article ; Online: Physicochemical aspects of the tumour microenvironment as drivers of vasculogenic mimicry.

Andreucci, Elena / Peppicelli, Silvia / Ruzzolini, Jessica / Bianchini, Francesca / Calorini, Lido

2022 Volume 41, Issue 4, Page(s) 935–951

Abstract: Tumour vascularisation is vital for cancer sustainment representing not only the main source of nutrients and oxygen supply but also an escape route for single or clustered cancer cells that, once detached from the primary mass, enter the blood ... ...

Abstract	Tumour vascularisation is vital for cancer sustainment representing not only the main source of nutrients and oxygen supply but also an escape route for single or clustered cancer cells that, once detached from the primary mass, enter the blood circulation and disseminate to distant organs. Among the mechanisms identified to contribute to tumour vascularisation, vasculogenic mimicry (VM) is gaining increasing interest in the scientific community representing an intriguing target for cancer treatment. VM indeed associates with highly aggressive tumour phenotypes and strongly impairs patient outcomes. Differently from vessels of healthy tissues, tumour vasculature is extremely heterogeneous and tortuous, impeding efficient chemotherapy delivery, and at the meantime hyperpermeable and thus extremely accessible to metastasising cancer cells. Moreover, tumour vessel disorganisation creates a self-reinforcing vicious circle fuelling cancer malignancy and progression. Because of the inefficient oxygen delivery and metabolic waste removal from tumour vessels, many cells within the tumour mass indeed experience hypoxia and acidosis, now considered hallmarks of cancer. Being strong inducers of vascularisation, therapy resistance, inflammation and metastasis, hypoxia and acidosis create a permissive microenvironment for cancer progression and dissemination. Along with these considerations, we decided to focus our attention on the relationship between hypoxia/acidosis and VM. Indeed, besides tumour angiogenesis, VM is strongly influenced by both hypoxia and acidosis, which could potentiate each other and fuel this vicious circle. Thus, targeting hypoxia and acidosis may represent a potential target to treat VM to impair tumour perfusion and cancer cell sustainment.
MeSH term(s)	Humans ; Tumor Microenvironment ; Neovascularization, Pathologic/pathology ; Neoplasms/pathology ; Hypoxia/metabolism ; Oxygen/therapeutic use
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2022-10-13
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	604857-2
ISSN	1573-7233 ; 0167-7659
ISSN (online)	1573-7233
ISSN	0167-7659
DOI	10.1007/s10555-022-10067-x
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Article ; Online: Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGF

Andreucci, Elena / Bugatti, Kelly / Peppicelli, Silvia / Ruzzolini, Jessica / Lulli, Matteo / Calorini, Lido / Battistini, Lucia / Zanardi, Franca / Sartori, Andrea / Bianchini, Francesca

International journal of molecular sciences

2023 Volume 24, Issue 2

Abstract: Growth factors and cytokines released in the lung cancer microenvironment promote an epithelial-to-mesenchymal transition (EMT) that sustains the progression of neoplastic diseases. ... ...

Abstract	Growth factors and cytokines released in the lung cancer microenvironment promote an epithelial-to-mesenchymal transition (EMT) that sustains the progression of neoplastic diseases. TGF
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/pathology ; Transforming Growth Factor beta/metabolism ; Ligands ; Lung Neoplasms/drug therapy ; Lung Neoplasms/pathology ; Integrins/metabolism ; Antineoplastic Agents/pharmacology ; Epithelial-Mesenchymal Transition ; Cell Line, Tumor ; Tumor Microenvironment
Chemical Substances	Transforming Growth Factor beta ; integrin alphavbeta6 ; nintedanib (G6HRD2P839) ; Ligands ; Integrins ; Antineoplastic Agents
Language	English
Publishing date	2023-01-12
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/ijms24021475
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Article: Oleuropein, a Bioactive Compound from

Nediani, Chiara / Ruzzolini, Jessica / Romani, Annalisa / Calorini, Lido

Antioxidants (Basel, Switzerland)

2019 Volume 8, Issue 12

Abstract: Growing scientific literature data suggest that the intake of natural bioactive compounds plays a critical role in preventing or reducing the occurrence of human chronic non-communicable diseases (NCDs). Oleuropein, the main phenolic component ... ...

Abstract	Growing scientific literature data suggest that the intake of natural bioactive compounds plays a critical role in preventing or reducing the occurrence of human chronic non-communicable diseases (NCDs). Oleuropein, the main phenolic component of
Language	English
Publishing date	2019-11-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox8120578
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Article ; Online: Extracellular Lactic Acidosis of the Tumor Microenvironment Drives Adipocyte-to-Myofibroblast Transition Fueling the Generation of Cancer-Associated Fibroblasts.

Andreucci, Elena / Fioretto, Bianca Saveria / Rosa, Irene / Matucci-Cerinic, Marco / Biagioni, Alessio / Romano, Eloisa / Calorini, Lido / Manetti, Mirko

Cells

2023 Volume 12, Issue 6

Abstract: Lactic acidosis characterizes the tumor microenvironment (TME) and is involved in the mechanisms leading to cancer progression and dissemination through the reprogramming of tumor and local host cells (e.g., endothelial cells, fibroblasts, and immune ... ...

Abstract	Lactic acidosis characterizes the tumor microenvironment (TME) and is involved in the mechanisms leading to cancer progression and dissemination through the reprogramming of tumor and local host cells (e.g., endothelial cells, fibroblasts, and immune cells). Adipose tissue also represents a crucial component of the TME which is receiving increasing attention due to its pro-tumoral activity, however, to date, it is not known whether it could be affected by the acidic TME. Now, emerging evidence from chronic inflammatory and fibrotic diseases underlines that adipocytes may give rise to pathogenic myofibroblast-like cells through the adipocyte-to-myofibroblast transition (AMT). Thus, our study aimed to investigate whether extracellular acidosis could affect the AMT process, sustaining the acquisition by adipocytes of a cancer-associated fibroblast (CAF)-like phenotype with a pro-tumoral activity. To this purpose, human subcutaneous adipose-derived stem cells committed to adipocytes (acADSCs) were cultured under basal (pH 7.4) or lactic acidic (pH 6.7, 10 mM lactate) conditions, and AMT was evaluated with quantitative PCR, immunoblotting, and immunofluorescence analyses. We observed that lactic acidosis significantly impaired the expression of adipocytic markers while inducing myofibroblastic, pro-fibrotic, and pro-inflammatory phenotypes in acADSCs, which are characteristic of AMT reprogramming. Interestingly, the conditioned medium of lactic acidosis-exposed acADSC cultures was able to induce myofibroblastic activation in normal fibroblasts and sustain the proliferation, migration, invasion, and therapy resistance of breast cancer cells in vitro. This study reveals a previously unrecognized relationship between lactic acidosis and the generation of a new CAF-like cell subpopulation from adipocytic precursor cells sustaining tumor malignancy.
MeSH term(s)	Humans ; Myofibroblasts/metabolism ; Cancer-Associated Fibroblasts/metabolism ; Acidosis, Lactic/metabolism ; Acidosis, Lactic/pathology ; Tumor Microenvironment ; Endothelial Cells/metabolism ; Adipocytes/metabolism ; Neoplasms/metabolism ; Lactic Acid/metabolism
Chemical Substances	Lactic Acid (33X04XA5AT)
Language	English
Publishing date	2023-03-20
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/cells12060939
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Article ; Online: FDG uptake in cancer: a continuing debate.

Peppicelli, Silvia / Andreucci, Elena / Ruzzolini, Jessica / Bianchini, Francesca / Calorini, Lido

Theranostics

2020 Volume 10, Issue 7, Page(s) 2944–2948

MeSH term(s)	Cell Line ; Drug Resistance, Neoplasm ; Fluorodeoxyglucose F18/adverse effects ; Glycolysis ; Humans ; Neoplasms/diagnostic imaging ; Neoplasms/therapy ; Oxygen/metabolism ; Positron-Emission Tomography/adverse effects ; Radiopharmaceuticals/adverse effects ; Tumor Microenvironment ; Warburg Effect, Oncologic/radiation effects
Chemical Substances	Radiopharmaceuticals ; Fluorodeoxyglucose F18 (0Z5B2CJX4D) ; Oxygen (S88TT14065)
Language	English
Publishing date	2020-02-06
Publishing country	Australia
Document type	Editorial
ZDB-ID	2592097-2
ISSN	1838-7640 ; 1838-7640
ISSN (online)	1838-7640
ISSN	1838-7640
DOI	10.7150/thno.40599
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Article ; Online: Extracellular Lactic Acidosis of the Tumor Microenvironment Drives Adipocyte-to-Myofibroblast Transition Fueling the Generation of Cancer-Associated Fibroblasts

Elena Andreucci / Bianca Saveria Fioretto / Irene Rosa / Marco Matucci-Cerinic / Alessio Biagioni / Eloisa Romano / Lido Calorini / Mirko Manetti

Cells, Vol 12, Iss 939, p

2023 Volume 939

Abstract	Lactic acidosis characterizes the tumor microenvironment (TME) and is involved in the mechanisms leading to cancer progression and dissemination through the reprogramming of tumor and local host cells (e.g., endothelial cells, fibroblasts, and immune cells). Adipose tissue also represents a crucial component of the TME which is receiving increasing attention due to its pro-tumoral activity, however, to date, it is not known whether it could be affected by the acidic TME. Now, emerging evidence from chronic inflammatory and fibrotic diseases underlines that adipocytes may give rise to pathogenic myofibroblast-like cells through the adipocyte-to-myofibroblast transition (AMT). Thus, our study aimed to investigate whether extracellular acidosis could affect the AMT process, sustaining the acquisition by adipocytes of a cancer-associated fibroblast (CAF)-like phenotype with a pro-tumoral activity. To this purpose, human subcutaneous adipose-derived stem cells committed to adipocytes (acADSCs) were cultured under basal (pH 7.4) or lactic acidic (pH 6.7, 10 mM lactate) conditions, and AMT was evaluated with quantitative PCR, immunoblotting, and immunofluorescence analyses. We observed that lactic acidosis significantly impaired the expression of adipocytic markers while inducing myofibroblastic, pro-fibrotic, and pro-inflammatory phenotypes in acADSCs, which are characteristic of AMT reprogramming. Interestingly, the conditioned medium of lactic acidosis-exposed acADSC cultures was able to induce myofibroblastic activation in normal fibroblasts and sustain the proliferation, migration, invasion, and therapy resistance of breast cancer cells in vitro. This study reveals a previously unrecognized relationship between lactic acidosis and the generation of a new CAF-like cell subpopulation from adipocytic precursor cells sustaining tumor malignancy.
Keywords	adipocytes ; adipose-derived stem cells ; cell differentiation ; extracellular acidosis ; lactate ; myofibroblasts ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Extracellular Acidosis Differentially Regulates Estrogen Receptor β-Dependent EMT Reprogramming in Female and Male Melanoma Cells.

Peppicelli, Silvia / Ruzzolini, Jessica / Lulli, Matteo / Biagioni, Alessio / Bianchini, Francesca / Caldarella, Adele / Nediani, Chiara / Andreucci, Elena / Calorini, Lido

International journal of molecular sciences

2022 Volume 23, Issue 23

Abstract: Clinical outcomes of melanoma patients pointed out a gender disparity that supports a correlation between sex hormone activity on estrogen receptors (ER) and melanoma development and progression. Here, we found that the epithelial-to-mesenchymal ... ...

Abstract	Clinical outcomes of melanoma patients pointed out a gender disparity that supports a correlation between sex hormone activity on estrogen receptors (ER) and melanoma development and progression. Here, we found that the epithelial-to-mesenchymal transition (EMT) of melanoma cells induced by extracellular acidosis, which is a crucial hallmark of solid cancers, correlates with the expression of ERβ, the most representative ER on melanoma cells. Extracellular acidosis induces an enhanced expression of ERβ in female cells and EMT markers remain unchanged, while extracellular acidosis did not induce the expression of ERβ in male cells and EMT was strongly promoted. An inverse relationship between ERβ expression and EMT markers in melanoma cells of different sex exposed to extracellular acidosis was revealed by two different technical approaches: florescence-activated cell sorting of high ERβ expressing cell subpopulations and ERβ receptor silencing. Finally, we found that ERβ regulates EMT through NF-κB activation. These results demonstrate that extracellular acidosis drives a differential ERβ regulation in male and female melanoma cells and that this gender disparity might open new perspectives for personalized therapeutic approaches.
Language	English
Publishing date	2022-12-06
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/ijms232315374
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Article: Cancer Glycolytic Dependence as a New Target of Olive Leaf Extract.

Ruzzolini, Jessica / Peppicelli, Silvia / Bianchini, Francesca / Andreucci, Elena / Urciuoli, Silvia / Romani, Annalisa / Tortora, Katia / Caderni, Giovanna / Nediani, Chiara / Calorini, Lido

Cancers

2020 Volume 12, Issue 2

Abstract: Oleuropein (Ole), the main bioactive phenolic component ... ...

Abstract	Oleuropein (Ole), the main bioactive phenolic component of
Language	English
Publishing date	2020-01-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12020317
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Article ; Online: The CAIX inhibitor SLC-0111 exerts anti-cancer activity on gastric cancer cell lines and resensitizes resistant cells to 5-Fluorouracil, taxane-derived, and platinum-based drugs.

Cancer letters

2023 Volume 571, Page(s) 216338

Abstract: Gastric cancer (GC) is the fifth most frequent malignancy and the fourth leading cause of worldwide cancer-related death. Despite the usage of multimodal perioperative chemotherapy (pCT), GC progressively gains chemoresistance, thereby, the ... ...

Abstract	Gastric cancer (GC) is the fifth most frequent malignancy and the fourth leading cause of worldwide cancer-related death. Despite the usage of multimodal perioperative chemotherapy (pCT), GC progressively gains chemoresistance, thereby, the identification of suitable targets to overcome drug resistance is fundamental. Amongst the potential biomarkers, carbonic anhydrase IX (CAIX) - associated with a poor prognosis of several solid cancers - has gained the most attention. In a cohort of GC patients who received perioperative FLOT (i.e., Leucovorin, 5-Fluouracil, Docetaxel, and Oxaliplatin) or FOLFOX (i.e., Leucovorin, 5-Fluouracil, and Oxaliplatin), non-responder patients showed an increased expression of tumor CAIX compared to responder group. Moreover, GC cell lines induced to be resistant to 5-Fluouracil, Paclitaxel, Cisplatin, or the combination of 5-Fluorouracil, Oxaliplatin, and Docetaxel, overexpressed CAIX compared to the control. Accordingly, CAIX-high-expressing GC cells showed increased therapy resistance compared to low-expressing cells. Notably, SLC0111 significantly improved the therapy response of both wild-type and resistant GC cells. Overall, these data suggest a correlation between CAIX and GC drug resistance highlighting the potential of SLC-0111 in re-sensitizing GC cells to pCT.
MeSH term(s)	Humans ; Antigens, Neoplasm/metabolism ; Antineoplastic Agents/pharmacology ; Carbonic Anhydrase Inhibitors/pharmacology ; Carbonic Anhydrase IX/genetics ; Carbonic Anhydrase IX/metabolism ; Cell Line ; Docetaxel/pharmacology ; Fluorouracil/pharmacology ; Leucovorin/pharmacology ; Oxaliplatin/pharmacology ; Stomach Neoplasms/drug therapy ; Stomach Neoplasms/pathology ; Taxoids/pharmacology ; Taxoids/therapeutic use ; Cell Line, Tumor
Chemical Substances	Antigens, Neoplasm ; Antineoplastic Agents ; Carbonic Anhydrase Inhibitors ; Carbonic Anhydrase IX (EC 4.2.1.1) ; Docetaxel (15H5577CQD) ; Fluorouracil (U3P01618RT) ; Leucovorin (Q573I9DVLP) ; Oxaliplatin (04ZR38536J) ; SLC-0111 ; taxane (1605-68-1) ; Taxoids
Language	English
Publishing date	2023-08-06
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2023.216338
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Article: An Oleocanthal-Enriched EVO Oil Extract Induces the ROS Production in Gastric Cancer Cells and Potentiates the Effect of Chemotherapy.

Peri, Sara / Ruzzolini, Jessica / Urciuoli, Silvia / Versienti, Giampaolo / Biagioni, Alessio / Andreucci, Elena / Peppicelli, Silvia / Bianchini, Francesca / Bottari, Andrea / Calorini, Lido / Nediani, Chiara / Magnelli, Lucia / Papucci, Laura

Antioxidants (Basel, Switzerland)

2022 Volume 11, Issue 9

Abstract: Oleocanthal, a minor polar compound in extra-virgin olive (EVO) oil, contains anticancer properties, which should be encouraged in its use in oncology. Gastric Cancer (GC), a very aggressive human cancer, is often diagnosed at advanced stages, when ... ...

Abstract	Oleocanthal, a minor polar compound in extra-virgin olive (EVO) oil, contains anticancer properties, which should be encouraged in its use in oncology. Gastric Cancer (GC), a very aggressive human cancer, is often diagnosed at advanced stages, when surgery is substituted or supported by chemotherapy (CT). However, CT frequently fails due to the patient's resistance to the treatment. Thus, the aim of this study is to verify whether an OC-enriched EVO oil extract fraction (OCF) may be useful in order to overcome a resistance to GC. We evaluated the OCF effects on an AGS gastric adenocarcinoma cell line wild type (AGS wt) and on its subpopulations resistant to 5-fluorouracil (5FUr), Paclitaxel (TAXr) or cisplatin (CISr). We found that a 60 µM dose of the OCF acts on the AGS wt, 5FUr and TAXr, leading to the cell cycle inhibition and to a ROS production, but not on CISr cells. Resistance of CISr to the OCF seems to be due to higher levels of antioxidant-enzymes that can counteract the OCF-induced ROS production. Moreover, using the OCF plus 5-fluorouracil, Paclitaxel or cisplatin, we found a potentiating effect compared with a mono-treatment in all resistant GC cells, including CISr. In conclusion, the use of the OCF in the management of GC has shown very interesting advantages, opening-up the possibility to evaluate the efficacy of the OCF in vivo, as a valid adjuvant in the treatment of resistant GC.
Language	English
Publishing date	2022-09-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox11091762
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