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2021 - Cancer stem cells and macrophages: molecular connections and future perspectives against cancer. [Articolo su rivista]
Aramini, Beatrice; Masciale, Valentina; Grisendi, Giulia; Banchelli, Federico; D'Amico, Roberto; Maiorana, Antonino; Morandi, Uliano; Dominici, Massimo; Husnain Haider, Khawaja

Cancer stem cells (CSCs) have been considered the key drivers of cancer initiation and progression due to their unlimited self-renewal capacity and their ability to induce tumor formation. Macrophages, particularly tumor-associated macrophages (TAMs), establish a tumor microenvironment to protect and induce CSCs development and dissemination. Many studies in the past decade have been performed to understand the molecular mediators of CSCs and TAMs, and several studies have elucidated the complex crosstalk that occurs between these two cell types. The aim of this review is to define the complex crosstalk between these two cell types and to highlight potential future anti-cancer strategies.

2021 - Molecular mechanisms and cellular contribution from lung fibrosis to lung cancer development. [Articolo su rivista]
Samarelli, Anna Valeria; Masciale, Valentina; Aramini, Beatrice; Pamela Colò, Georgina; Tonelli, Roberto; Marchioni, Alessandro; Bruzzi, Giulia; Gozzi, Filippo; Andrisani, Dario; Castaniere, Ivana; Manicardi, Linda; Moretti, Antonio; Tabbì, Luca; Guaitoli, Giorgia; Cerri, Stefania; Dominici, Massimo; Clini, Enrico

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung 28 disease (ILD) of unknown etiology, with a median survival of 2-4 years from the time of diagnosis. 29 Although IPF has unknown etiology by definition, there have been identified several risks factors 30 increasing the probability of the onset and progression of the disease in IPF patients such as cigarette 31 smoking and environmental risks factors associated to domestic and occupational exposure. Among 32 them, cigarette smoking together with concomitant emphysema might predispose IPF patients to 33 lung cancer (LC), mostly to non-small cell lung cancer (NSCLC), increasing the risk of lung cancer 34 development. To this purpose, IPF and LC share several cellular and molecular processes driving 35 the progression of both pathologies such as fibroblast transition proliferation and activation, endo- 36 plasmic reticulum stress, oxidative stress, and many genetic and epigenetic markers that predispose 37 the IPF patients to LC development. Nintedanib, a tyrosine-kinase inhibitor, was firstly developed 38 as an anticancer drug and then recognized as an anti-fibrotic agent based on the common target 39 molecular pathway. In this review our aim is to describe the updated studies on common cellular 40 and molecular mechanisms between IPF and lung cancer, whose knowledge might help to find 41 novel therapeutic targets for this disease combination.

2021 - New Perspectives in Different Gene Expression Profiles for Early and Locally Advanced Non-Small Cell Lung Cancer Stem Cells. [Articolo su rivista]
Masciale, Valentina; Banchelli, Federico; Grisendi, Giulia; D'Amico, Roberto; Maiorana, Antonino; Stefani, Alessandro; Morandi, Uliano; Dominici, Massimo; Aramini, Beatrice

Introduction: Lung cancer is one of the most common cancers in the world, causing over 1.7 million deaths in 2018. Thus far, no effective treatments against lung cancer for advanced stages have been found. For early stages, although surgery is considered the gold standard treatment, 30–55% of patients develop recurrence within the first 5 years of surgery. Our aim is to assess whether cancer stem cells (CSC) display overexpression of a pool of genes that were previously identified for adenocarcinoma recurrence in patients with early and locally advanced stages of non-small cell lung cancer (NSCLC). Methods: This cross-sectional study was carried out by harvesting surgical tumor specimens obtained from patients harboring early (I-II) and locally advanced (IIIA) stages of NSCLC. For each patient, cell sorting was performed to identify and isolate the ALDHhigh (CSC) and ALDHlow (cancer cells) populations. The mRNA expressions of 31 recurrence-related genes (target genes) in both ALDHhigh and ALDHlow populations were then assessed and compared. Results: Surgical specimens were obtained from 22 patients harboring NSCLC. Sixteen (51.6%) out of 31 recurrence-related genes were significantly overexpressed in ALDHhigh cells in the early stages and 9 (29.0%) were overexpressed in the locally advanced stages of NSCLC. Overall, the relative mRNA expressions for these recurrence-related genes were higher in early-stage patients. The average fold change, considering all 31 recurrence-related genes together, was 4.5 (95% CI = 3.1-6.3) in early-stage patients and 1.6 (95% CI = 1.2-2.2) in locally advanced-stage patients. Conclusions: Our study represents the first attempt toward identifying genes associated with recurrence that are overexpressed in cancer stem cells in patients with early and ocally advanced stages of NSCLC. This finding may contribute to the identification of new target therapies tailored for NSCLC stages.

2021 - Use of Octreotide in association with talc poudrage for the management of a severe chylothorax: A case report [Articolo su rivista]
Lovati, Eleonora; Ruggiero, Ciro; Masciale, Valentina; Stefani, Alessandro; Morandi, Uliano; Aramini, Beatrice

Chylothorax is an uncommon form of pleural effusion characterized by the presence of chylomicrons, triglycerides and cholesterol in the physical and chemical examination of the pleural fluid. It may have poor prognosis if not properly treated. Currently, conservative measures are the first line of treatment for managing chylothorax. The aim of our study is to show and suggest the use of octreotide in association with talc poudrage as good option to manage post-operative a severe chylothorax.

2020 - ALDH Expression in Angiosarcoma of the Lung: A Potential Marker of Aggressiveness? [Articolo su rivista]
Aramini, Beatrice; Masciale, Valentina; Bianchi, Daniel; Manfredini, Beatrice; Banchelli, Federico; D'Amico, Roberto; Bertolini, Federica; Dominici, Massimo; Morandi, Uliano; Maiorana, Antonino

Background: Primary angiosarcoma of the lung is a very aggressive rare malignant disease resulting in a severe prognosis (1). This type of cancer represents about 2% of all soft tissue sarcomas and has a high rate of metastasis through the hematogenous route. For the rarity of this malignant vascular tumor it is still challenging to set a diagnosis (1). The diagnostic features that have thus far been considered include primarily clinical and radiological findings. In some cases, immunohistochemical characteristics based on the most common markers used in pathology have been described. The aim of this report is to present two cases of angiosarcoma of the lung in which the aldehyde dehydrogenase (ALDH) marker was analyzed by immunohistochemistry. Methods: We report two cases of angiosarcoma of the lung in patients underwent lung surgery at our Unit. In addition to the standard histopathological analysis for this disease, immunohistochemistry using an ALDH1A1 antibody was performed in both of the cases. For ALDH quantification, a semi-quantitative method based on the positivity of the tumor cells was used: 0 (<5%), 1 (5–25%), 2 (>25–50%), 3 (>50–75%), 4 (>75%). Results: One patient with recurrent lung disease survived, achieving complete remission after chemo- and radiotherapy. The second patient died of recurrent disease within 5 years of diagnosis. ALDH1A1 was evaluated in both of these cases using an immunohistochemistry scoring system based on the positivity for this marker. The scores were consistent with the patients’ clinical outcomes, as the lower (score 1) was observed in the patient with the better clinical outcome, while the higher (score 3) was seen in the patient with the worse outcome. Conclusion: Our data suggest that ALDH may be an important clinical marker in angiosarcoma of the lung. Although further studies need to be performed in a larger cohort of patients, we believe that, if the results will be confirmed, ALDH1A1 may be used to stratify patients in terms of prognosis and for targeted therapy.

2020 - Arming Mesenchymal Stromal/Stem Cells Against Cancer: Has the Time Come? [Articolo su rivista]
Golinelli, Giulia; Mastrolia, Ilenia; Aramini, Beatrice; Masciale, Valentina; Pinelli, Massimo; Pacchioni, Lucrezia; Casari, Giulia; Dall'Ora, Massimiliano; Botelho Pereira Soares, Milena; Kauanna Fonseca Damasceno, Patrícia; Nascimento Silva, Daniela; Dominici, Massimo; Grisendi, Giulia

Since mesenchymal stromal/stem cells (MSCs) were discovered, researchers have been drawn to study their peculiar biological features, including their immune privileged status and their capacity to selectively migrate into inflammatory areas, including tumors. These properties make MSCs promising cellular vehicles for the delivery of therapeutic molecules in the clinical setting. In recent decades, the engineering of MSCs into biological vehicles carrying anticancer compounds has been achieved in different ways, including the loadingof MSCs with chemotherapeutics or drug functionalized nanoparticles (NPs), genetic modifications to force the production of anticancer proteins, and the use of oncolytic viruses. Recently, it has been demonstrated that wild-type and engineered MSCs can release extracellular vesicles (EVs) that contain therapeutic agents. Despite the enthusiasm for MSCs as cyto-pharmaceutical agents, many challenges, including controlling the fate of MSCs after administration, must still be considered. Preclinical results demonstrated that MSCs accumulate in lung, liver, and spleen, which could prevent their engraftment into tumor sites. For this reason, physical, physiological, and biological methods have been implemented to increase MSC concentration in the target tumors. Currently, there are more than 900 registered clinical trials using MSCs. Only a small fraction of these are investigating MSC-based therapies for cancer, but the number of these clinical trials is expected to increase as technology and our understanding of MSCs improve. This review will summarize MSC-based antitumor therapies to generate an increasing awareness of their potential and limits to accelerate their clinical translation.

2020 - CD44+/EPCAM+ cells detect a subpopulation of ALDHhigh cells in human non-small cell lung cancer: A chance for targeting cancer stem cells? [Articolo su rivista]
Masciale, Valentina; Grisendi, Giulia; Banchelli, Federico; D'Amico, Roberto; Maiorana, Antonino; Sighinolfi, Pamela; Stefani, Alessandro; Morandi, Uliano; Dominici, Massimo; Aramini, Beatrice

Objectives: Several studies demonstrated that aldehyde dehydrogenase (ALDH) and CD44 are the most considered cancer stem cells (CSC) markers. However, a comparison between ALDH high cells and CD44+ cells have been previously described with no significant correlation. Indeed, the aim of the present research is to identify a superficial marker able to match with ALDH high cells population in freshly isolated human lung cancer cells. Materials and Methods: This cross-sectional study analyzed the expression of ALDHhigh/low cells and the positivity for CD44 and epithelium cell adhesion molecule (EPCAM) antigens in surgical lung cancer tissues. The main approach was a cytofluorimetric analysis of ALDH expression and positivity for CD44/EPCAM on primary cell population obtained from 23 patients harboring NSCLC. Results: There was a highly positive correlation between the expressions of ALDHhigh and CD44+/EPCAM+ cells, with a Pearson’s correlation coefficient equal to 0.69 (95% CI 0.39–0.86; P = 0.0002), and Spearman’s correlation coefficient equal to 0.52 (P = 0.0124). The average paired difference between the expression of ALDHhigh and CD44+/EPCAM+ cells was very close to 0, being 0.1% (SD 2.5%); there was no difference between these subpopulations in terms of means (95% CI = –1.0; 1.2%, P = 0.8464). These results highlight a strong similarity between ALDHhigh and CD44+/EPCAM+ cells. Conclusions: Our study is the first attempt which identifies a high correlation between the ALDHhigh and the CD44+/EPCAM+ cells, thus suggesting the possibility to use this superficial marker for future target treatments against lung cancer stem cells.

2020 - Cancer Stem-Like Cells in a Case of an Inflammatory Myofibroblastic Tumor of the Lung. [Articolo su rivista]
Masciale, Valentina; Grisendi, Giulia; Banchelli, Federico; D'Amico, Roberto; Maiorana, Antonino; Sighinolfi, Pamela; Brugioni, Lucio; Stefani, Alessandro; Morandi, Uliano; Dominici, Massimo; Aramini, Beatrice

Background: Inflammatory myofibroblast tumor (IMT) is a rare tumor with obscure etiopathogenesis in which different inflammatory cells and myofibroblastic spindle cells are seen histologically. Although the majority of these neoplasms have a benign clinical course, the malignant form has also been reported. The gold standard is surgical treatment for complete removal. Our report describes a 50-year-old woman who underwent surgery for IMT of the lung. The aim is to determine whether cancer stem cells may be present in IMT of the lung. Methods: In April 2018, the patient underwent surgery for tumor mass asportation through lateral thoracotomy. The histology of the tumor was consistent with IMT of the lung. The ALDEFLUOR assay, after tissue digestion, was used to identify and sort human lung cancer cells expressing high and low aldehyde dehydrogenase (ALDH) activity. SOX2, NANOG, OCT-4, and c-MYC positivity were additionally determined by immunohistochemistry. Results: The specimen contained 1.10% ALDHhigh cells among all viable lung cancer cells, which indicates the population of cancer stem cells is not negligible. Immunohistochemically assessed cell positivity for ALDH1A1, SOX2, NANOG, OCT-4, and c-MYC, which are considered as lung cancer stem-like cells markers. Conclusion: For the first time, we demonstrated the presence of cancer stem cells in a case of IMT of the lung. This finding may provide a base for considering new pathological and molecular aspects of this tumor. This perspective suggests further studies to understand the possibility of developing recurrence depending on the presence of cancer stem cells.

2020 - Defining lung cancer stem cells exosomal payload of miRNAs in clinical perspective. [Articolo su rivista]
Aramini, Beatrice; Masciale, Valentina; Husnain Haider, Khawaja

Since the first publication regarding the existence of stem cells in cancer [cancer stem cells (CSCs)] in 1994, many studies have been published providing in-depth information about their biology and function. This research has paved the way in terms of appreciating the role of CSCs in tumour aggressiveness, progression, recurrence and resistance to cancer therapy. Targeting CSCs for cancer therapy has still not progressed to a sufficient degree, particularly in terms of exploring the mechanism of dynamic interconversion between CSCs and non-CSCs. Besides the CSC scenario, the problem of cancer dissemination has been analyzed in-depth with the identification and isolation of microRNAs (miRs), which are now considered to be compelling molecular markers in the diagnosis and prognosis of tumours in general and specifically in patients with non-small cell lung cancer. Paracrine release of miRs via “exosomes” (small membrane vesicles (30-100 nm), the derivation of which lies in the luminal membranes of multi-vesicular bodies) released by fusion with the cell membrane is gaining popularity. Whether exosomes play a significant role in maintaining a dynamic equilibrium state between CSCs and non-CSCs and their mechanism of activity is as yet unknown. Future studies on CSC-related exosomes will provide new perspectives for precision-targeted treatment strategies.

2020 - Expression of ALDH and SOX-2 in Pulmonary Sclerosing Pnemocytoma (PSP) of the Lung: Is There a Meaning Behind? [Articolo su rivista]
Aramini, Beatrice; Masciale, Valentina; Manfredini, Beatrice; Bianchi, Daniel; Banchelli, Federico; D'Amico, Roberto; Bertolini, Federica; Dominici, Massimo; Morandi, Uliano; Maiorana, Antonino

Background: Pulmonary sclerosing pneumocytoma (PSP) is a rare benign pulmonary tumor that derives from primitive respiratory epithelium of the pulmonary alveolus. The etiology and pathogenesis are still unclear. Histopathological diagnosis focuses on cells that are positive for TTF1, EMA, cytokeratin-7, and CAM 5.2. The aim of our study is to highlight the elevated expression of ALDH and the presence of SOX-2 in pulmonary sclerosing pneumocytoma. Methods: We report five cases of pulmonary sclerosing pneumocytoma undergone surgery at our Division of Thoracic Surgery, during a period between 1994 and 2011. ALDH and SOX-2 markers were also tested for positivity in all the patients. Results: Patients showed elevated expression of ALDH during immunohistochemistry and mild expression of SOX-2, although in two cases in which SOX-2 was highly expressed. Among these two patients, one presented with lymph node recurrence while the other had no recurrence with a PET-positive nodule. In particular, the patient who had developed recurrence had an ALDH score of 4 and a SOX-2 score of 3, whereas the patient with the PET-positive nodule showed an ALDH score of 4 with a mild SOX-2expression of score 1. Conclusions: This is the first attempt demonstrating the elevated expression of ALDH in this disease. SOX-2 expression was noted in both the patient who developed recurrence and the patient with a PET-positive nodule. We believe that further investigation may be highly useful to better characterize these two markers as well as understandtheir function.

2020 - Overall survival in patients with lung adenocarcinoma harboring "niche" mutations: an observational study [Articolo su rivista]
Aramini, Beatrice; Banchelli, Federico; Bettelli, Stefania Raffaella; Manfredini, Samantha; D'Amico, Roberto; Masciale, Valentina; Pinelli, Massimo; Moretti Fantera, Margherita; Stefani, Alessandro; Bertolini, Federica; Dominici, Massimo; Morandi, Uliano; Maiorana, Antonino

Objective: In addition to the most common somatic lung cancer mutations (i. e., KRAS and EGFR mutations), other genes may harbor mutations that could be relevant for lung cancer. We defined BRAF, c-MET, DDR2, HER2, MAP2K1, NRAS, PIK3CA, and RET mutations as “niche” mutations and analyzed. The aim of this retrospective cohort study was to assess the differences in the overall survival (OS) of patients with lung adenocarcinoma harboring niche somatic mutations. Results: Data were gathered for 252 patients. Mutations were observed in all genes studied, except c-MET, DDR2, MAP2K1, and RET. The multivariable analysis showed that 1) niche mutations had a higher mortality than EGFR mutations (HR = 2.3; 95% CI = 1.2–4.4; p = 0.009); 2) KRAS mutations had a higher mortality than EGFR mutations (HR = 2.5; 95% CI = 1.4–4.5; p = 0.003); 3) niche mutations presented a similar mortality to KRAS mutations (HR = 0.9; 95% CI = 0.6–1.5; p = 0.797). Methods: Three cohorts of mutations were selected from patients with lung adenocarcinoma and their OS was compared. Mutations that were searched for, were 1) BRAF, c-MET, DDR2, HER2, MAP2K1, NRAS, PIK3CA, and RET; 2) K-RAS; and 3) EGFR. Differences in OS between these three cohorts were assessed by means of a multivariable Cox model that adjusted for age, sex, smoking habits, clinical stages, and treatments. Conclusions: Niche mutations exhibited an increased risk of death when compared with EGFR mutations and a similar risk of death when compared with KRAS mutations.

2020 - Precision Medicine in Lung Cancer: Challenges and Opportunities in Diagnostic and Therapeutic Purposes. [Capitolo/Saggio]
Aramini, Beatrice; Masciale, Valentina; Banchelli, Federico; D'Amico, Roberto; Dominici, Massimo; Husnain Haider, Khawaja

Lung cancer is one of the leading causes of cancer death among both men and women, making up almost 25% of all cancer deaths. Precision medicine shows promise for improving many aspects of health and healthcare, including tests, drugs, and other technologies that support innovation, with the possibility of new partnerships with scientists in a wide range of specialties. Non–small-cell lung cancer (NSCLC) has become a prominent example of the success of precision medicine in treating solid tumor malignancies. The first step in this process involves new bloodbased diagnostics, which can now noninvasively provide clinically useful information. However, the identification of novel biomarkers that could be used in early diagnosis is urgently needed, especially for guiding initial therapy and predicting relapse or drug resistance following the administration of novel targeted therapies.

2019 - A Novel 3D In Vitro Platform for Pre-Clinical Investigations in Drug Testing, Gene Therapy, and Immuno-oncology. [Articolo su rivista]
Candini, O; Grisendi, G; Foppiani, Em; Brogli, M; Aramini, B; Masciale, V; Spano, C; Petrachi, T; Veronesi, E; Conte, P; Mari, G; Dominici, M.

Tumors develop within complex cell-to-cell interactions, with accessory cells playing a relevant role starting in the early phases of cancer progression. This event occurs in a three-dimensional (3D) environment, which to date, has been difficult to reproduce in vitro due to its complexity. While bi-dimensional cultures have generated substantial data, there is a progressive awareness that 3D culture strategies may rapidly increase the understanding of tumor development and be used in anti-cancer compound screening and for predicting response to new drugs utilizing personalized approaches. However, simple systems capable of rapidly rebuilding cancer tissues ex-vivo in 3D are needed and could be used for a variety of applications. Therefore, we developed a flat, handheld and versatile 3D cell culture bioreactor that can be loaded with tumor and/or normal cells in combination which can be monitored using a variety of read-outs. This biocompatible device sustained 3D growth of tumor cell lines representative of various cancers, such as pancreatic and breast adenocarcinoma, sarcoma, and glioblastoma. The cells repopulated the thin matrix which was completely separated from the outer space by two gas-permeable membranes and was monitored in real-time using both microscopy and luminometry, even after transportation. The device was tested in 3D cytotoxicity assays to investigate the anti-cancer potential of chemotherapy, biologic agents, and cell-based therapy in co-cultures. The addition of luciferase in target cancer cells is suitable for comparative studies that may also involve parallel in vivo investigations. Notably, the system was challenged using primary tumor cells harvested from lung cancer patients as an innovative predictive functional assay for cancer responsiveness to checkpoint inhibitors, such as nivolumab. This bioreactor has several novel features in the 3D-culture field of research, representing a valid tool useful for cancer investigations, drug screenings, and other toxicology approaches.

2019 - Cancer stem-neuroendocrine cells in an atypical carcinoid case report. [Articolo su rivista]
MASCIALE, VALENTINA; GRISENDI, Giulia; BANCHELLI, FEDERICO; D'AMICO, Roberto; MAIORANA, Antonino; Morandi1, Uliano; DOMINICI, Massimo; Aramini, Beatrice

Lung neuroendocrine cells tumor (NET) classification and diagnosis, particularly for typical and atypical carcinoids, are complicated by a variable natural history and nonspecific symptoms. Mechanisms for the development and progression of well-differentiated lung NETs are still unclear. An accurate and timely diagnosis can ensure the implementation of appropriate treatment and impact on prognosis. One of the main unclear point is the definition of these cells’ composition. In fact, it is known that carcinoids are mainly constituted by neuroendocrine cells. Aim of our report is to show for the first time the presence of a high percentage of cancer stem cells (CSCs) in an atypical carcinoid. The ALDEFLUOR assay was used to identify and sort ALDHhigh and ALDHlow human lung cancer cells following tissue digestion. SOX2 was additionally determined by immunohistochemistry. All specimens contained the 53.10% of ALDHhigh cells among all viable lung cancer cells, which indicates that more than half of the entire tumor cell population was composed by CSCs. As expected also in immunohistochemistry, about a half of the nuclei of the cells were positive for SOX2. We strongly support the hypothesis of the presence of cancer stem-neuroendocrine cells (CSCs-NETs) as subpopulation in these types of tumors.

2019 - Correlating tumor-infiltrating lymphocytes and lung cancer stem cells: a cross-sectional study. [Articolo su rivista]
MASCIALE, VALENTINA; GRISENDI, Giulia; BANCHELLI, FEDERICO; D'AMICO, Roberto; MAIORANA, Antonino; SIGHINOLFI, Pamela; PINELLI, MASSIMO; Lovati, Eleonora; STEFANI, Alessandro; MORANDI, Uliano; DOMINICI, Massimo; Aramini, Beatrice

Background: Lung cancer stem cells (LCSCs) are endowed with high aldehyde dehydrogenase (ALDH) expression and play roles in tumor proliferation, metastasis, and drug resistance. Their elusive nature may allow them to escape the immune response by tumor-infiltrating lymphocytes (TILs), which can positively affect the outcome in non-small cell lung cancer (NSCLC) patients. Despite independent investigations on both LCSCs and TILs, the relationship between the two has been very marginally considered. We analyzed whether these two cell types may be related as a prerequisite for novel diagnostic and therapeutic approaches. Methods: In this cross-sectional study, NSCLC human surgical specimens from 12 patients were tested by ALDEFLUOR assay to identify ALDHhigh cells. Fluorescence-activated cell sorting (FACS) analyses for CD3+, CD4+, and CD8+ TILs were performed in combination with immunohistochemistry evaluation. Results: Statistically positive correlations were found between ALDH+ and CD8+, and between ALDH+ and CD3+ cells populations; no correlation was found between ALDH+ and CD4+ cells. The expression of CD3+ and CD8+ by cells accounted for 40.1% and 58.7%, respectively, of the variability of ALDH+ cell expression by an R-squared index, which highlights the strong correlation between TILs and LCSCs. Immunohistochemistry revealed 6–25% positive cells. Conclusions: We report a correlation between cytotoxic TILs and LCSCs, which may contribute to the future development of targeted therapies focusing on the different roles of lymphocytes against lung cancer.

2019 - Isolation and Identification of Cancer Stem-Like Cells in Adenocarcinoma and Squamous Cell Carcinoma of the Lung: A Pilot Study [Articolo su rivista]
Masciale, Valentina; Grisendi, Giulia; Banchelli, Federico; D'Amico, Roberto; Maiorana, Antonino; Sighinolfi, Pamela; Stefani, Alessandro; Morandi, Uliano; Dominici, Massimo; Aramini, Beatrice

Background: Lung cancer stem cells (CSCs) share many characteristics with normal stem cells, such as self-renewal and multipotentiality. High expression of aldehyde dehydrogenase (ALDH) has been detected in many tumors, particularly in the CSC compartment, and it plays an important role in tumor proliferation, metastasis, and drug resistance. CD44 is commonly used as a cell surface marker of cancer stem-like cells in epithelial tumors. The aim of this study was to isolate and analyze cancer stem-like cells from surgically removed specimens to compare lung adenocarcinoma (ADENO) and squamous (SQUAMO) cell carcinoma. Methods: The ALDEFLUOR assay was used to identify and sort ALDHhigh and ALDHlow human lung cancer cells following tissue digestion. Fluorescence-activated cell sorting analysis for CD44 was performed with tumor cells. Quantitative real-time PCR was performed to assess the expression of SOX2 and NANOG as stemness markers. ALDH1A1 expression was additionally determined by immunohistochemistry. Anchorage-independent ALDHhigh cell growth was also evaluated. ALDHhigh ADENO and SQUAMO cells were cultured to analyze spheroid formation. Results: All specimens contained 0.5–12.5% ALDHhigh cells with 3.8–18.9% CD44-positive cells. SOX2 and NANOG relative expression in ALDHhigh compared to ALDHlow cells in ADENO and SQUAMO was analyzed and compared between the histotypes. Immunohistochemistry confirmed the presence of ALDH1A1 in the sections. SOX2 and NANOG were expressed at higher levels in the ALDHhigh subpopulation than in the ALDHlow subpopulation only in ADENO cells, and the opposite result was seen in SQUAMO cells. In vitro functional assays demonstrated that ALDHhigh cells exhibited migration capacity with distinct behaviors between ALDHhigh spheres in ADENO vs. SQUAMO samples. Conclusions: Our results highlight the importance of a better characterization of cancer stem-like cells in ADENO and SQUAMO histotypes. This may suggest new differential approaches for prognostic and therapeutic purposes in patients with non-small-cell lung cancer.

2019 - Stem cells and lung cancer : between advanced diagnostics and new therapeutics. [Capitolo/Saggio]
Masciale, V; Grisendi, G; Morandi, U; Dominici, M; Aramini, B.

Lung cancers (LCs) remain a significant and devastating cause of morbidity and mortality worldwide. Despite the very recent success of immunotherapy, the diagnosis and treatment of LC remain one of the greatest challenges in chest surgery, clinical oncology, and molecular medicine. A growing number of investigations on normal/cancer stem cells and cellular therapies are offering exciting new avenues to advance knowledge on LC. Here, we will be focusing on the multiple relationships between LC and stem cells accounting for cancer stem cell (CSC) diagnostics and progenitor-based therapeutics for LC. Cancer cell repopulation after chemotherapy and/or radiotherapy still represents a major factor limiting the efficacy of treatment since CSCs play critical roles during this process by reciprocal connections between CSCs and tumor microenvironment. This calls for new opportunities to integrate advanced CSC diagnostics and targeted approaches also based on immunotherapy. In addition, recent discoveries on malignant pleural and other LC highlight that mesenchymal stromal/stem cells may be a novel platform for drug delivery within still unexplored gene therapy strategies. This chapter will dissect these two apparently distant technologies within a unified stem-cell-based vision aimed at providing better diagnostics and therapeutics for LC at the forefront of modern clinical oncology.

2018 - Cancer stem cells and their microenvironment. [Capitolo/Saggio]
MASCIALE, VALENTINA; GRISENDI, Giulia; BANCHELLI, FEDERICO; D'AMICO, Roberto; MORANDI, Uliano; DOMINICI, Massimo; Husnain Haider, Khawaja; Aramini, Beatrice

2018 - Challenging the efficacy of checkpoint inhibitors: a new 3D model for a precision medicine approach. [Abstract in Atti di Convegno]
Foppiani, ELISABETTA MANUELA; Candini, Olivia; Aramini, Beatrice; Masciale, Valentina; Grisendi, Giulia; Matteo, Brogli; Giorgio, Mari; Dominici, Massimo

Challenging the efficacy of checkpoint inhibitors: a new 3D model for a precision medicine approach.