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Article: Editorial: Tailoring immunotherapy in gastrointestinal cancer: the role of circulating factors.

Ugel, Stefano / Bazzichetto, Chiara / Conciatori, Fabiana

2023 Volume 13, Page(s) 1260183

Language	English
Publishing date	2023-08-08
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1260183
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Translational Landscape of mTOR Signaling in Integrating Cues Between Cancer and Tumor Microenvironment.

Bazzichetto, Chiara / Conciatori, Fabiana / Falcone, Italia / Ciuffreda, Ludovica

Advances in experimental medicine and biology

2020 Volume 1223, Page(s) 69–80

Abstract: The mammalian target of rapamycin (mTOR) represents a critical hub for the regulation of different processes in both normal and tumor cells. Furthermore, it is now well established the role of mTOR in integrating and shaping different environmental ... ...

Abstract	The mammalian target of rapamycin (mTOR) represents a critical hub for the regulation of different processes in both normal and tumor cells. Furthermore, it is now well established the role of mTOR in integrating and shaping different environmental paracrine and autocrine stimuli in tumor microenvironment (TME) constituents. Recently, further efforts have been employed to understand how the mTOR signal transduction mechanisms modulate the sensitivity and resistance to targeted therapies, also for its involvement of mTOR also in modulating angiogenesis and tumor immunity. Indeed, interest in mTOR targeting was increased to improve immune response against cancer and to develop new long-term efficacy strategies, as demonstrated by clinical success of mTOR and immune checkpoint inhibitor combinations. In this chapter, we will describe the role of mTOR in modulating TME elements and the implication in its targeting as a great promise in clinical trials.
MeSH term(s)	Humans ; Neoplasms/drug therapy ; Neoplasms/immunology ; Neoplasms/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/immunology ; TOR Serine-Threonine Kinases/metabolism ; Tumor Microenvironment/drug effects
Chemical Substances	MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1)
Language	English
Publishing date	2020-02-07
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-35582-1_4
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Article: Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy.

Falcone, Italia / Conciatori, Fabiana / Bazzichetto, Chiara / Ferretti, Gianluigi / Cognetti, Francesco / Ciuffreda, Ludovica / Milella, Michele

Cancers

2020 Volume 12, Issue 10

Abstract: Antitumor therapies have made great strides in recent decades. Chemotherapy, aggressive and unable to discriminate cancer from healthy cells, has given way to personalized treatments that, recognizing and blocking specific molecular targets, have paved ... ...

Abstract	Antitumor therapies have made great strides in recent decades. Chemotherapy, aggressive and unable to discriminate cancer from healthy cells, has given way to personalized treatments that, recognizing and blocking specific molecular targets, have paved the way for targeted and effective therapies. Melanoma was one of the first tumor types to benefit from this new care frontier by introducing specific inhibitors for v-Raf murine sarcoma viral oncogene homolog B (BRAF), mitogen-activated protein kinase (MEK), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and, recently, immunotherapy. However, despite the progress made in the melanoma treatment, primary and/or acquired drug resistance remains an unresolved problem. The molecular dynamics that promote this phenomenon are very complex but several studies have shown that the tumor microenvironment (TME) plays, certainly, a key role. In this review, we will describe the new melanoma treatment approaches and we will analyze the mechanisms by which TME promotes resistance to targeted therapy and immunotherapy.
Language	English
Publishing date	2020-10-06
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12102870
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Article ; Online: Colorectal cancer stem cells properties and features: evidence of interleukin-8 involvement.

Conciatori, Fabiana / Bazzichetto, Chiara / Falcone, Italia / Ferretti, Gianluigi / Cognetti, Francesco / Milella, Michele / Ciuffreda, Ludovica

Cancer drug resistance (Alhambra, Calif.)

2019 Volume 2, Issue 4, Page(s) 968–979

Abstract: Colorectal cancer (CRC) still remains a disease with high percentage of death, principally due to therapy resistance and metastasis. During the time the hypothesis has been reinforced that CRC stem cells (CRCSC) are involved in allowing intratumoral ... ...

Abstract	Colorectal cancer (CRC) still remains a disease with high percentage of death, principally due to therapy resistance and metastasis. During the time the hypothesis has been reinforced that CRC stem cells (CRCSC) are involved in allowing intratumoral heterogeneity, drug escape mechanisms and secondary tumors. CRCSC are characterized by specific surface markers (i.e., CD44 and CD133), signaling pathways activation (i.e., Wnt and Notch) and gene expression (i.e., Oct4 and Snail), which confer to CRCSC self-renewal abilities and pluripotent capacity. Interleukin (IL)-8 is correlated to CRC progression, development of liver metastases and chemoresistance; moreover, IL-8 modulates not only stemness maintenance but also stemness promotion, such as epithelial-mesenchymal transition. This review wants to give a brief and up-to-date overview on IL-8 implication in CRCSC cues.
Language	English
Publishing date	2019-12-19
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2578-532X
ISSN (online)	2578-532X
DOI	10.20517/cdr.2019.56
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Article: The Key Roles of PTEN in T-Cell Acute Lymphoblastic Leukemia Development, Progression, and Therapeutic Response.

Martelli, Alberto M / Paganelli, Francesca / Fazio, Antonietta / Bazzichetto, Chiara / Conciatori, Fabiana / McCubrey, James A

Cancers

2019 Volume 11, Issue 5

Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer that comprises 10-15% of pediatric and ~25% of adult ALL cases. Although the curative rates have significantly improved over the past 10 years, especially in pediatric patients, T- ... ...

Abstract	T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer that comprises 10-15% of pediatric and ~25% of adult ALL cases. Although the curative rates have significantly improved over the past 10 years, especially in pediatric patients, T-ALL remains a challenge from a therapeutic point of view, due to the high number of early relapses that are for the most part resistant to further treatment. Considerable advances in the understanding of the genes, signaling networks, and mechanisms that play crucial roles in the pathobiology of T-ALL have led to the identification of the key drivers of the disease, thereby paving the way for new therapeutic approaches. PTEN is critical to prevent the malignant transformation of T-cells. However, its expression and functions are altered in human T-ALL.
Language	English
Publishing date	2019-05-06
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers11050629
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Article: Advances in Tumor-Stroma Interactions: Emerging Role of Cytokine Network in Colorectal and Pancreatic Cancer.

Bazzichetto, Chiara / Conciatori, Fabiana / Falcone, Italia / Cognetti, Francesco / Milella, Michele / Ciuffreda, Ludovica

Journal of oncology

2019 Volume 2019, Page(s) 5373580

Abstract: Cytokines are a family of soluble factors (Growth Factors (GFs), chemokines, angiogenic factors, and interferons), which regulate a wide range of mechanisms in both physiological and pathological conditions, such as tumor cell growth and progression, ... ...

Abstract	Cytokines are a family of soluble factors (Growth Factors (GFs), chemokines, angiogenic factors, and interferons), which regulate a wide range of mechanisms in both physiological and pathological conditions, such as tumor cell growth and progression, angiogenesis, and metastasis. In recent years, the growing interest in developing new cancer targeted therapies has been accompanied by the effort to characterize Tumor Microenvironment (TME) and Tumor-Stroma Interactions (TSI). The connection between tumor and stroma is now well established and, in the last decade, evidence from genetic, pharmacological, and epidemiological data supported the importance of microenvironment in tumor progression. However, several of the mechanisms behind TSI and their implication in tumor progression remain still unclear and it is crucial to establish their potential in determining pharmacological response. Many studies have demonstrated that cytokines network can profoundly affect TME, thus displaying potential therapeutic efficacy in both preclinical and clinical models. The goal of this review is to give an overview of the most relevant cytokines involved in colorectal and pancreatic cancer progression and their implication in drug response.
Language	English
Publishing date	2019-05-05
Publishing country	Egypt
Document type	Journal Article ; Review
ZDB-ID	2461349-6
ISSN	1687-8469 ; 1687-8450
ISSN (online)	1687-8469
ISSN	1687-8450
DOI	10.1155/2019/5373580
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Article: Interleukin-8 in Colorectal Cancer: A Systematic Review and Meta-Analysis of Its Potential Role as a Prognostic Biomarker.

Bazzichetto, Chiara / Milella, Michele / Zampiva, Ilaria / Simionato, Francesca / Amoreo, Carla Azzurra / Buglioni, Simonetta / Pacelli, Chiara / Le Pera, Loredana / Colombo, Teresa / Bria, Emilio / Zeuli, Massimo / Del Bufalo, Donatella / Sperduti, Isabella / Conciatori, Fabiana

Biomedicines

2022 Volume 10, Issue 10

Abstract: Among soluble actors that have emerged as druggable factors, the chemokine interleukin-8 (IL-8) has emerged as a possible determinant of response to immunotherapy and targeted treatment in several cancer types; however, its prognostic/predictive role in ... ...

Abstract	Among soluble actors that have emerged as druggable factors, the chemokine interleukin-8 (IL-8) has emerged as a possible determinant of response to immunotherapy and targeted treatment in several cancer types; however, its prognostic/predictive role in colorectal cancer (CRC) remains to be established. We: (i) conducted a systematic review of published literature on IL-8 expression in CRC; (ii) searched public transcriptomics databases; (iii) investigated IL-8 expression, by tumor and infiltrating cells, in a series of CRC samples; and (iv) carried out a meta-analysis of published literature correlating IL-8 expression and CRC prognosis. IL-8 possesses an important role as a mediator of the bidirectional crosstalk between tumor/stromal cells. Transcriptomic analysis indicated that specific IL-8 transcripts were significantly overexpressed in CRC compared to normal colon mucosa. Moreover, in our series we observed a statistically significant correlation between PTEN-loss and IL-8 expression by infiltrating mononuclear and tumor cells. In total, 12 papers met our meta-analysis inclusion criteria, demonstrating that high IL-8 levels significantly correlated with shorter overall survival and progression-free survival. Sensitivity analysis demonstrated a highly significant correlation with outcome for circulating, but not for tissue-detected, IL-8. IL-8 is overexpressed in CRC tissues and differentially produced by tumor or stromal components depending on CRC genetic background. Moreover, circulating IL-8 represents a strong prognostic factor in CRC, suggesting its use in the refining of prognostic CRC assessment and potentially the tailoring of therapeutic strategies in individual CRC patients.
Language	English
Publishing date	2022-10-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10102631
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Article: Fibroblast-Induced Paradoxical PI3K Pathway Activation in PTEN-Competent Colorectal Cancer: Implications for Therapeutic PI3K/mTOR Inhibition.

Conciatori, Fabiana / Salvati, Erica / Ciuffreda, Ludovica / Shirasawa, Senji / Falcone, Italia / Cognetti, Francesco / Ferretti, Gianluigi / Zeuli, Massimo / Del Bufalo, Donatella / Bazzichetto, Chiara / Milella, Michele

Frontiers in oncology

2022 Volume 12, Page(s) 862806

Abstract: Purpose: Tumor-microenvironment interactions are important determinants of drug resistance in colorectal cancer (CRC). We, therefore, set out to understand how interactions between genetically characterized CRC cells and stromal fibroblasts might ... ...

Abstract	Purpose: Tumor-microenvironment interactions are important determinants of drug resistance in colorectal cancer (CRC). We, therefore, set out to understand how interactions between genetically characterized CRC cells and stromal fibroblasts might influence response to molecularly targeted inhibitors. Techniques: Sensitivity to PI3K/AKT/mTOR pathway inhibitors of CRC cell lines, with known genetic background, was investigated under different culture conditions [serum-free medium, fibroblasts' conditioned medium (CM), direct co-culture]. Molecular pathway activation was monitored using Western Blot analysis. Immunoprecipitation was used to detect specific mTOR complex activation. Immunofluorescence was used to analyze cellular PTEN distribution, while different mutant PTEN plasmids were used to map the observed function to specific PTEN protein domains. Results: Exposure to fibroblast-CM resulted in increased growth-inhibitory response to double PI3K/mTOR inhibitors in PTEN-competent CRC cell lines harboring Data interpretation: Microenvironmental cues, in particular soluble factors produced by stromal fibroblasts, profoundly influence PI3K pathway signaling and functional response to specific inhibitors in CRC cells, depending on their mutational background and PTEN status.
Language	English
Publishing date	2022-06-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.862806
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Article ; Online: AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations.

Falcone, Italia / Conciatori, Fabiana / Bazzichetto, Chiara / Bria, Emilio / Carbognin, Luisa / Malaguti, Paola / Ferretti, Gianluigi / Cognetti, Francesco / Milella, Michele / Ciuffreda, Ludovica

International journal of molecular sciences

2020 Volume 21, Issue 22

Abstract: Breast cancer was one of the first malignancies to benefit from targeted therapy, i.e., treatments directed against specific markers. Inhibitors against HER2 are a significant example and they improved the life expectancy of a large cohort of patients. ... ...

Abstract	Breast cancer was one of the first malignancies to benefit from targeted therapy, i.e., treatments directed against specific markers. Inhibitors against HER2 are a significant example and they improved the life expectancy of a large cohort of patients. Research on new biomarkers, therefore, is always current and important. AXL, a member of the TYRO-3, AXL and MER (TAM) subfamily, is, today, considered a predictive and prognostic biomarker in many tumor contexts, primarily breast cancer. Its oncogenic implications make it an ideal target for the development of new pharmacological agents; moreover, its recent role as immune-modulator makes AXL particularly attractive to researchers involved in the study of interactions between cancer and the tumor microenvironment (TME). All these peculiarities characterize AXL as compared to other members of the TAM family. In this review, we will illustrate the biological role played by AXL in breast tumor cells, highlighting its molecular and biological features, its involvement in tumor progression and its implication as a target in ongoing clinical trials.
MeSH term(s)	Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor/antagonists & inhibitors ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/physiology ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/physiopathology ; Cell Movement/genetics ; Cell Movement/physiology ; Drug Resistance, Neoplasm ; Epithelial-Mesenchymal Transition/drug effects ; Epithelial-Mesenchymal Transition/genetics ; Epithelial-Mesenchymal Transition/physiology ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Intercellular Signaling Peptides and Proteins/chemistry ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/physiology ; Molecular Targeted Therapy/methods ; Neoplasm Invasiveness/genetics ; Neoplasm Invasiveness/physiopathology ; Protein Kinase Inhibitors/therapeutic use ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/physiology ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/physiology ; Tumor Microenvironment/genetics ; Tumor Microenvironment/physiology
Chemical Substances	Antineoplastic Agents ; Biomarkers, Tumor ; Intercellular Signaling Peptides and Proteins ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins ; growth arrest-specific protein 6 ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; axl receptor tyrosine kinase (EC 2.7.10.1)
Language	English
Publishing date	2020-11-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21228419
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Article ; Online: PTEN Function at the Interface between Cancer and Tumor Microenvironment: Implications for Response to Immunotherapy.

Conciatori, Fabiana / Bazzichetto, Chiara / Falcone, Italia / Ciuffreda, Ludovica / Ferretti, Gianluigi / Vari, Sabrina / Ferraresi, Virginia / Cognetti, Francesco / Milella, Michele

International journal of molecular sciences

2020 Volume 21, Issue 15

Abstract: Mounting preclinical and clinical evidence indicates that rewiring the host immune system in favor of an antitumor microenvironment achieves remarkable clinical efficacy in the treatment of many hematological and solid cancer patients. Nevertheless, ... ...

Abstract	Mounting preclinical and clinical evidence indicates that rewiring the host immune system in favor of an antitumor microenvironment achieves remarkable clinical efficacy in the treatment of many hematological and solid cancer patients. Nevertheless, despite the promising development of many new and interesting therapeutic strategies, many of these still fail from a clinical point of view, probably due to the lack of prognostic and predictive biomarkers. In that respect, several data shed new light on the role of the tumor suppressor phosphatase and tensin homolog on chromosome 10 (PTEN) in affecting the composition and function of the tumor microenvironment (TME) as well as resistance/sensitivity to immunotherapy. In this review, we summarize current knowledge on PTEN functions in different TME compartments (immune and stromal cells) and how they can modulate sensitivity/resistance to different immunological manipulations and ultimately influence clinical response to cancer immunotherapy.
MeSH term(s)	Humans ; Immunotherapy ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; PTEN Phosphohydrolase/immunology ; Tumor Microenvironment/immunology
Chemical Substances	PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67)
Language	English
Publishing date	2020-07-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21155337
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