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Understanding the diversity in cancer research priorities and the correlations among different treatment modalities is essential to address the evolving landscape of oncology. This study, conducted in collaboration with the European Cancer Patient Coalition (ECPC) and Childhood Cancer International-Europe (CCI-E) as part of the "UNCAN.eu" initiative, analyzed data from a comprehensive survey to explore the complex interplay of demographics, time since cancer diagnosis, and types of treatments received. Demographic analysis revealed intriguing trends, highlighting the importance of tailoring cancer research efforts to specific age groups and genders. Individuals aged 45-69 exhibited highly aligned research priorities, emphasizing the need to address the unique concerns of middle-aged and older populations. In contrast, patients over 70 years demonstrated a divergence in research priorities, underscoring the importance of recognising the distinct needs of older individuals in cancer research. The analysis of correlations among different types of cancer treatments underscored the multidisciplinary approach to cancer care, with surgery, radiotherapy, chemotherapy, precision therapy, and biological therapies playing integral roles. These findings support the need for personalized and combined treatment strategies to achieve optimal outcomes. In conclusion, this study provides valuable insights into the complexity of cancer research priorities and treatment correlations in a European context. It emphasizes the importance of a multifaceted, patient-centred approach to cancer research and treatment, highlighting the need for ongoing support, adaptation, and collaboration to address the ever-changing landscape of oncology.

To enable a collective effort that generates a new level of UNderstanding CANcer (UNCAN.eu) [Cancer Discov (2022) 12 (11): OF1], the European Union supports the creation of a sustainable platform that connects cancer research across Member States. A workshop hosted in Heidelberg gathered European cancer experts to identify ongoing initiatives that may contribute to building this platform and discuss the governance and long-term evolution of a European Federated Cancer Data Hub., (©2023 The Authors; Published by the American Association for Cancer Research.)

Cancer immunotherapy is the great breakthrough in cancer treatment as it displayed prolonged progression-free survival over conventional therapies, yet, to date, in only a minority of patients. In order to broad cancer immunotherapy clinical applicability some roadblocks need to be overcome, first among all the lack of preclinical models that faithfully depict the local tumor microenvironment (TME), which is known to dramatically affect disease onset, progression and response to therapy. In this review, we provide the reader with a detailed overview of current 3D models developed to mimick the complexity and the dynamics of the TME, with a focus on understanding why the TME is a major target in anticancer therapy. We highlight the advantages and translational potentials of tumor spheroids, organoids and immune Tumor-on-a-Chip models in disease modeling and therapeutic response, while outlining pending challenges and limitations. Thinking forward, we focus on the possibility to integrate the know-hows of micro-engineers, cancer immunologists, pharmaceutical researchers and bioinformaticians to meet the needs of cancer researchers and clinicians interested in using these platforms with high fidelity for patient-tailored disease modeling and drug discovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Manduca, Maccafeo, De Maria, Sistigu and Musella.)

The biological complexity of cancer represents a tremendous clinical challenge, resulting in the frequent failure of current treatment protocols. In the rapidly evolving scenario of a growing tumor, anticancer treatments impose a drastic perturbation not only to cancer cells but also to the tumor microenvironment, killing a portion of the cells and inducing a massive stress response in the survivors. Consequently, treatments can act as a double-edged sword by inducing a temporary response while laying the ground for therapy resistance and subsequent disease progression. Cancer cell dormancy (or quiescence) is a central theme in tumor evolution, being tightly linked to the tumor's ability to survive cytotoxic challenges, metastasize, and resist immune-mediated attack. Accordingly, quiescent cancer cells (QCCs) have been detected in virtually all the stages of tumor development. In recent years, an increasing number of studies have focused on the characterization of quiescent/therapy resistant cancer cells, unveiling QCCs core transcriptional programs, metabolic plasticity, and mechanisms of immune escape. At the same time, our partial understanding of tumor quiescence reflects the difficulty to identify stable QCCs biomarkers/therapeutic targets and to control cancer dormancy in clinical settings. This review focuses on recent discoveries in the interrelated fields of dormancy, stemness, and therapy resistance, discussing experimental evidences in the frame of a nonlinear dynamics approach, and exploring the possibility that tumor quiescence may represent not only a peril but also a potential therapeutic resource., (© 2023. The Author(s).)

Cancer cell dormancy is a common feature of human tumors and represents a major clinical barrier to the long-term efficacy of anticancer therapies. Dormant cancer cells, either in primary tumors or disseminated in secondary organs, may reawaken and relapse into a more aggressive disease. The mechanisms underpinning dormancy entry and exit strongly resemble those governing cancer cell stemness and include intrinsic and contextual cues. Cellular and molecular components of the tumor microenvironment persistently interact with cancer cells. This dialog is highly dynamic, as it evolves over time and space, strongly cooperates with intrinsic cell nets, and governs cancer cell features (like quiescence and stemness) and fate (survival and outgrowth). Therefore, there is a need for deeper insight into the biology of dormant cancer (stem) cells and the mechanisms regulating the equilibrium quiescence- versus -proliferation are vital in our pursuit of new therapeutic opportunities to prevent cancer from recurring. Here, we review and discuss microenvironmental regulations of cancer dormancy and its parallels with cancer stemness, and offer insights into the therapeutic strategies adopted to prevent a lethal recurrence, by either eradicating resident dormant cancer (stem) cells or maintaining them in a dormant state., (Copyright © 2020 Sistigu, Musella, Galassi, Vitale and De Maria.)

In the last decades, the role of the microenvironment in tumor progression and therapeutic outcome has gained increasing attention. Cancer-associated fibroblasts (CAFs) have emerged as key players among stromal cells, owing to their abundance in most solid tumors and their diverse tumor-restraining/promoting roles. The interplay between tumor cells and neighboring CAFs takes place by both paracrine signals (cytokines, exosomes and metabolites) or by the multifaceted functions of the surrounding extracellular matrix. Here, we dissect the most recent identified mechanisms underlying CAF-mediated control of tumor progression and therapy resistance, which include induction of the epithelial-to-mesenchymal transition (EMT), activation of survival pathways or stemness-related programs and metabolic reprogramming in tumor cells. Importantly, the recently unveiled heterogeneity in CAFs claims tailored therapeutic efforts aimed at eradicating the specific subset facilitating tumor progression, therapy resistance and relapse. However, despite the large amount of pre-clinical data, much effort is still needed to translate CAF-directed anti-cancer strategies from the bench to the clinic.

Cancer stem cells (CSCs) are subpopulations of multipotent stem cells (SCs) responsible for the initiation, long-term clonal maintenance, growth and spreading of most human neoplasms. Reportedly, CSCs share a very robust DNA damage response (DDR) with embryonic and adult SCs, which allows them to survive endogenous and exogenous genotoxins. A range of experimental evidence indicates that CSCs have high but heterogeneous levels of replication stress (RS), arising from, and being boosted by, endogenous causes, such as specific genetic backgrounds (e.g., p53 deficiency) and/or aberrant karyotypes (e.g., supernumerary chromosomes). A multipronged RS response (RSR) is put in place by CSCs to limit and ensure tolerability to RS. The characteristics of such dedicated cascade have two opposite consequences, both relevant for cancer therapy. On the one hand, RSR efficiency often increases the reliance of CSCs on specific DDR components. On the other hand, the functional redundancy of pathways of the RSR can paradoxically promote the acquisition of resistance to RS- and/or DNA damage-inducing agents. Here, we provide an overview of the molecular mechanisms of the RSR in cancer cells and CSCs, focusing on the role of CHK1 and some emerging players, such as PARP1 and components of the homologous recombination repair, whose targeting can represent a long-term effective anti-CSC strategy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The Hippo pathway is a central regulator of organ size and tissue homeostasis. Hippo kinases and adaptor proteins mediate the phosphorylation and inactivation of YAP and TAZ, two closely related transcription co-activators. The Hippo pathway responds to a variety of extracellular and intracellular signals, spanning from cell-cell contact and mechanical cues to ligands of G-protein-coupled receptors and metabolic avenues. In some instances, YAP/TAZ activation is tuned by forces that bypass the Hippo kinase module, adding further complexity to the biology of the pathway. Over the past two decades, the Hippo pathway has increasingly been connected with developmental processes and tissue repair, being intimately tied to the function of tissue-specific progenitor cells. Pervasive activation of YAP/TAZ has been recognized in a multitude of human tumors and connected with the acquisition of malignant traits, including resistance to anticancer therapies, distant dissemination and maintenance of cancer stem cells. On this ground, Hippo-related biomarkers are increasingly investigated in translational studies striving to identify prognostic and predictive factors. In addition, the dependency of many tumors on YAP/TAZ may be exploited for therapeutic purposes. Albeit no direct inhibitors are currently available, drug repositioning approaches provided hints that YAP/TAZ inhibition can be achieved with old drugs, such as cholesterol-lowering agents or compounds blocking bone resorption., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In the last few years, non-coding RNAs (ncRNAs) have been a hot topic in cancer research. Many ncRNAs were found to regulate the apoptotic process and to play a role in tumor cell resistance to treatment. The apoptotic program is on the frontline as self-defense from cancer onset, and evasion of apoptosis has been classified as one of the hallmarks of cancer responsible for therapy failure. The B-cell lymphoma 2 (BCL-2) family members are key players in the regulation of apoptosis and mediate the activation of the mitochondrial death machinery in response to radiation, chemotherapeutic agents and many targeted therapeutics. The balance between the pro-survival and the pro-apoptotic BCL-2 proteins is strictly controlled by ncRNAs. Here, we highlight the most common mechanisms exerted by microRNAs, long non-coding RNAs and circular RNAs on the main mediators of the intrinsic apoptotic cascade with particular focus on their significance in cancer biology., Competing Interests: The authors declare no conflict of interest.

Both embryonic and adult stem cells are endowed with a superior capacity to prevent the accumulation of genetic lesions, repair them, or avoid their propagation to daughter cells, which would be particularly detrimental to the whole organism. Inducible pluripotent stem cells also display a robust DNA damage response, but the stability of their genome is often conditioned by the mutational history of the cell population of origin, which constitutes an obstacle to clinical applications. Cancer stem cells are particularly tolerant to DNA damage and fail to undergo senescence or regulated cell death upon accumulation of genetic lesions. Such a resistance contributes to the genetic drift of evolving tumors as well as to their limited sensitivity to chemo- and radiotherapy. Here, we discuss the pathophysiological and therapeutic implications of the molecular pathways through which stem cells cope with DNA damage., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The conversion of cells with an epithelial phenotype into cells with a mesenchymal phenotype, referred to as epithelial-mesenchymal transition, is a critical process for embryonic development that also occurs in adult life, particularly during tumour progression. Tumour cells undergoing epithelial-mesenchymal transition acquire the capacity to disarm the body's antitumour defences, resist apoptosis and anticancer drugs, disseminate throughout the organism, and act as a reservoir that replenishes and expands the tumour cell population. Epithelial-mesenchymal transition is therefore becoming a target of prime interest for anticancer therapy. Here, we discuss the screening and classification of compounds that affect epithelial-mesenchymal transition, highlight some compounds of particular interest, and address issues related to their clinical application.

Alliance Against Cancer (ACC) was established in Rome in 2002 as a consortium of six Italian comprehensive cancer centers (Founders). The aims of ACC were to promote a network among Italian oncologic institutions in order to develop specific, advanced projects in clinical and translational research. During the following years, many additional full and associate members joined ACC, that presently includes the National Institute of Health, 17 research-oriented hospitals, scientific and patient organizations. Furthermore, in the last three years ACC underwent a reorganization process that redesigned the structure, governance and major activities. The present goal of ACC is to achieve high standards of care across Italy, to implement and harmonize principles of modern personalized and precision medicine, by developing cost effective processes and to provide tailored information to cancer patients. We herein summarize some of the major initiatives that ACC is currently developing to reach its goal, including tumor genetic screening programs, establishment of clinical trial programs for cancer patients treated in Italian cancer centers, facilitate their access to innovative drugs under development, improve quality through an European accreditation process (European Organization of Cancer Institutes), and develop international partnerships. In conclusion, ACC is a growing organization, trying to respond to the need of networking in Italy and may contribute significantly to improve the way we face cancer in Europe.

Cells with "stemness" and tumor-initiating properties have been isolated from both hematological and solid tumors. These cells denominated as cancer stem cells (CSCs), representing rare populations within tumors, have the ability to metastasize and are resistant to standard therapies and immunotherapy. Heterogeneity and plasticity in the phenotype of CSCs have been described in relation to their tissue origin. Few definitive markers have been isolated for CSCs from human solid tumors, limiting their usage for in vivo identification of these cells. Nevertheless, progress in the emerging CSCs concept has been achieved gaining, at least for some type of tumors, their biological and immunological characterization. The recent identification of molecules and signaling pathways that are up-regulated or aberrantly induced in CSCs allowed the development of small agents for specifically targeting of CSCs. A general low immunogenic profile has been reported for CSCs with, in some cases, the identification of the mechanisms responsible of the impairment of cell-mediated immune responses. These concepts are discussed in the context of this review. Although CSCs still need to be fully characterized, potential candidate markers and/or signaling pathways, to be exploited for the design of novel CSC-targeting therapeutic strategies, are described in this review.

Recent advances in experimental technologies and cancer models have made possible to demonstrate that the tumor is a dynamic system comprising heterogeneous populations of cancer cells organized in a hierarchical fashion with cancer stem cells (CSCs) at the apex. CSCs are immature cells characterized by self-renewal property and long-term repopulation potential. CSCs have been causally linked to cancer initiation, propagation, spreading, recurrence and relapse as well as to resistance to anticancer therapy. A growing body of evidence suggests that the function and physiology of CSCs may be influenced by genetic/epigenetic factors and tumor environment. In this context, macroautophagy is a lysosomal degradative process (herein referred to as autophagy) critical for the adaptive response to stress and the preservation of cellular and tissue homeostasis in all eukaryotes that may have a crucial role of in the origin, maintenance and invasiveness of CSCs. The activation of the autophagic machinery is also considered as an adaptive response of CSCs to perturbation of tumor microenvironment, caused for instance by anticancer therapy. Nevertheless, compelling preclinical and clinical evidence on the cytoprotective role of autophagy for CSCs is still missing. Here, we summarize the results on the contribution of autophagy in CSCs and how it impacts tumorigenesis and tumor progression. We also discuss the therapeutical potential of the modulation of autophagy as a means to eradicate CSCs.

Alleanza Contro il Cancro (Alliance Against Cancer (ACC)) is a network of excellence comprising cancer centers with high standard patient care and research supervised by the Italian Ministry of Health. Founded in 2002, ACC has recently entered a renovation process in order to further increase quality procedures and international standing of the network. The Organization of European Cancer Institutes (OECI) accreditation system contributes significantly to this renovation process, which is generally directed towards all the main activities of cancer care and research, but has a particular attention to the treatment of advanced cancers that cannot be cured by standard procedures in conventional hospitals.

Overcoming resistance to standard anticancer treatments represents a significant challenge. The interest regarding cancer stem cells, a cellular population that has the ability to self-renew and to propagate the tumor, was prompted by experimental evidence delineating the molecular mechanisms that are selectively activated in this cellular subset in order to survive chemotherapy. This has also stimulated combination strategies aimed at rendering cancer stem cells vulnerable to anticancer agents. Moreover, cancer stem cells offer a unique opportunity for modeling human cancers in mice, thus emerging as a powerful tool for testing novel drugs and combinations in a simulation of human disease. These novel animal models may lay the foundation for a new generation of clinical trials aimed at anticipating the benefit to patients of anticancer therapies.

Unlabelled: Let-7c, an intronic microRNA (miRNA) embedded in the long non-coding gene LINC00478, can act as a tumor suppressor by targeting oncogenes. Previous studies indicated that in acute promyelocytic leukemia (APL), a subtype of acute myelogenous leukemia (AML) bearing the leukemia promoting PML/RARα fusion protein, let-7c expression seems to be controlled by the host gene promoter, in which canonical Retinoic Acid Responsive Elements (RAREs) are bound by PML/RARα in an all transretinoic acid (ATRA)-sensitive manner. Here, let-7c transcriptional regulation was further investigated and a novel intronic promoter upstream of the pre-miRNA was identified. This new promoter has transcriptional activity strongly indicating that at least two promoters need to be considered for let-7c transcription: the distal host gene and the proximal intronic promoter. Therefore, epigenetic modifying enzymes and histone acetylation and methylation status were analyzed on both let-7c promoters. It was demonstrated that ATRA treatment leads to let-7c upregulation inducing a more open chromatin conformation of the host gene promoter, with an enrichment of epigenetic marks that correlate with a more active transcriptional state. Conversely, the epigenetic marks on the intronic promoter are not significantly affected by ATRA treatment. Interestingly, in solid tumors such as prostate and lung adenocarcinoma it was found that both host and intronic promoters are functional. These data suggest that while the host gene promoter may control let-7c expression in AML, in a nonleukemic tumor context instead the intronic promoter contributes or preferentially regulates let-7c transcription., Implications: Alternative promoter usage represents a regulatory mechanism of let-7c expression in different tissues. Mol Cancer Res; 12(6); 878-89. ©2014 AACR., (©2014 American Association for Cancer Research.)

The NCI-60 cell line set is likely the most molecularly profiled set of human tumor cell lines in the world. However, a critical missing component of previous analyses has been the inability to place the massive amounts of "-omic" data in the context of functional protein signaling networks, which often contain many of the drug targets for new targeted therapeutics. We used reverse-phase protein array (RPPA) analysis to measure the activation/phosphorylation state of 135 proteins, with a total analysis of nearly 200 key protein isoforms involved in cell proliferation, survival, migration, adhesion, etc., in all 60 cell lines. We aggregated the signaling data into biochemical modules of interconnected kinase substrates for 6 key cancer signaling pathways: AKT, mTOR, EGF receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), integrin, and apoptosis signaling. The net activation state of these protein network modules was correlated to available individual protein, phosphoprotein, mutational, metabolomic, miRNA, transcriptional, and drug sensitivity data. Pathway activation mapping identified reproducible and distinct signaling cohorts that transcended organ-type distinctions. Direct correlations with the protein network modules involved largely protein phosphorylation data but we also identified direct correlations of signaling networks with metabolites, miRNA, and DNA data. The integration of protein activation measurements into biochemically interconnected modules provided a novel means to align the functional protein architecture with multiple "-omic" data sets and therapeutic response correlations. This approach may provide a deeper understanding of how cellular biochemistry defines therapeutic response. Such "-omic" portraits could inform rational anticancer agent screenings and drive personalized therapeutic approaches., (©2013 AACR.)

There is a significant void in cancer biology with regard to the elucidation of the mechanisms that underlie tumor formation and progression. Recently, the existence of a hierarchy within cancer cell populations has been demonstrated experimentally for several tumor types. The identification of a tumor cell subset that is capable of self-renewal and, concurrently, generation into more differentiated progeny has engendered new perspectives toward selective targeting of tumors. Although the identification of the so-called "cancer stem cells" (CSCs) is a leap in the study of cancer ontogenesis, therapeutic targeting of such cells is plagued by significant difficulties. CSCs are able to evade the control mechanisms that regulate cell survival and proliferation. Apoptosis is one of the most critical and well-studied mechanisms, governing tissue development and homeostasis through a complex network of molecules that mediate death and survival signals. Escape from such a finely tuned death program is a prerequisite for any tumor-initiating cell. Thus, many compounds have been developed to target cancer cells and induce apoptosis directly or indirectly. Several TRAIL receptor agonists are in Phase I or II trials, and IAP inhibitors are undergoing clinical examination to exploit their ability to enhance ionizing radiation- and chemotherapy-induced apoptosis. Further, the EGF-R/Akt pro-survival signaling axis is one of the most frequently explored sources of targets for indirect apoptosis induction, as evidenced by the significant amount of molecules designed to target this pathway and have been approved by the FDA or are under clinical evaluation. Despite the promise of these magic bullets, the absence of reliable clinical models has considerably diminished the therapeutic potential of targeted therapies considerably. A more systematic molecular characterization of the tumor-initiating cell population in many tumors will allow us to refine the stimuli that force CSCs to die, thus accelerating the development of more effective treatment for cancer., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

With the advent of molecular targeted therapies and the development of high-throughput biotechnologies, it has become evident that progress in cancer research is largely due to the creation of multidisciplinary teams able to plan clinical trials supported by appropriate molecular hypotheses. These efforts have culminated in the identification and validation of biomarkers predictive of response, as well as in the generation of more accurate prognostic tools. The identification of cancer stem cells has provided further insights into mechanisms of cancer, and many studies have tried to translate this biological notion into prognostic and predictive information. In this regard, new agents targeting key stemness-related pathways have entered the clinical development, and preliminary data suggested an encouraging antitumor activity.

Background: PTX is one of the most widely used drug in oncology due to its high efficacy against solid tumors and several hematological cancers. PTX is administered in a formulation containing 1:1 Cremophor EL (polyethoxylated castor oil) and ethanol, often responsible for toxic effects. Its encapsulation in colloidal delivery systems would gain an improved targeting to cancer cells, reducing the dose and frequency of administration., Methods: In this paper PTX was loaded in PLGA NS. The activity of PTX-NS was assessed in vitro against thyroid, breast and bladder cancer cell lines in cultures. Cell growth was evaluated by MTS assay, intracellular NS uptake was performed using coumarin-6 labelled NS and the amount of intracellular PTX was measured by HPLC., Results: NS loaded with 3% PTX (w/w) had a mean size < 250 nm and a polydispersity index of 0.4 after freeze-drying with 0.5% HP-Cyd as cryoprotector. PTX encapsulation efficiency was 30% and NS showed a prolonged drug release in vitro. An increase of the cytotoxic effect of PTX-NS was observed with respect to free PTX in all cell lines tested., Conclusion: These findings suggest that the greater biological effect of PTX-NS could be due to higher uptake of the drug inside the cells as shown by intracellular NS uptake and cell accumulation studies.