Editorial: Recent 3D Tumor Models for Testing Immune-Mediated Therapies
Zimmer J, Castriconi R, Scaglione S.
» Abstract
This Research Topic is dedicated to some recent aspects of the 3D “revolution”, describing or reviewing in detail the different models. The articles likewise critically discuss the most relevant weaknesses of the 3D models, suggesting possible methodological approaches to address and resolve them.
Front Immunol. 2021 Nov 18;12:798493. doi: 10.3389/fimmu.2021.798493. PMID: 34868086; PMCID: PMC8637122.
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The osteo-angiogenic signaling crosstalk for bone regeneration: harmony out of complexity
Di Maggio N, Banfi A.
» Abstract
In recent years it has been increasingly appreciated that blood vessels are not simply suppliers of nutrients and oxygen, but actually play an exquisite regulatory role in bone development and repair. A specialized kind of endothelium, named type H because of its high expression of CD31 and Endomucin, constitutes anatomically defined vessels in proximity of the epiphyseal growth plate. Type H endothelium regulates the proliferation and differentiation of both osteoblasts and osteoclasts through the secretion of angiocrine signals and is a hub for the bidirectional molecular crosstalk between the different cell populations of the osteogenic microenvironment. Type H vessels are a key target for current translational approaches aiming at coupling angiogenesis and osteogenesis for bone repair. Open questions remain about their presence and features in notstereotyped tissues, like engineered osteogenic grafts, and the opportunities for their clinical stimulation by pharmacological treatments.
Curr Opin Biotechnol. 2022 Aug;76:102750. doi: 10.1016/j.copbio.2022.102750. Epub 2022 Jul 13. PMID: 35841865.
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The metastatic spread of breast cancer accelerates during sleep.
Diamantopoulou Z, Castro-Giner F, Schwab FD, Foerster C, Saini M, Budinjas S, Strittmatter K, Krol I, Seifert B, Heinzelmann-Schwarz V, Kurzeder C, Rochlitz C, Vetter M, Weber WP, Aceto N.
» Abstract
The metastatic spread of cancer is achieved by the hematogenous dissemination of circulating tumour cells (CTCs). Generally, however, the temporal dynamics that dictate the generation of metastasis-competent CTCs are largely uncharacterized, and it is often assumed that CTCs are constantly shed from growing tumours or are shed as a consequence of mechanical insults1. Here we observe a striking and unexpected pattern of CTC generation dynamics in both patients with breast cancer and mouse models, highlighting that most spontaneous CTC intravasation events occur during sleep. Further, we demonstrate that rest-phase CTCs are highly prone to metastasize, whereas CTCs generated during the active phase are devoid of metastatic ability. Mechanistically, single-cell RNA sequencing analysis of CTCs reveals a marked upregulation of mitotic genes exclusively during the rest phase in both patients and mouse models, enabling metastasis proficiency. Systemically, we find that key circadian rhythm hormones such as melatonin, testosterone and glucocorticoids dictate CTC generation dynamics, and as a consequence, that insulin directly promotes tumour cell proliferation in vivo, yet in a time-dependent manner. Thus, the spontaneous generation of CTCs with a high proclivity to metastasize does not occur continuously, but it is concentrated within the rest phase of the affected individual, providing a new rationale for time-controlled interrogation and treatment of metastasis-prone cancers.
Nature. 2022 Jul;607(7917):156-162. doi: 10.1038/s41586-022-04875-y. Epub 2022 Jun 22. PMID: 35732738.
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Clinical and Biological Aspects of Disseminated Tumor Cells and Dormancy in Breast Cancer
Ring A, Spataro M, Wicki A, Aceto N.
» Abstract
Progress in detection and treatment have drastically improved survival for early breast cancer patients. However, distant recurrence causes high mortality and is typically considered incurable. Cancer dissemination occurs via circulating tumor cells (CTCs) and up to 75% of breast cancer patients could harbor micrometastatses at time of diagnosis, while metastatic recurrence often occurs years to decades after treatment. During clinical latency, disseminated tumor cells (DTCs) can enter a state of cell cycle arrest or dormancy at distant sites, and are likely shielded from immune detection and treatment. While this is a challenge, it can also be seen as an outstanding opportunity to target dormant DTCs on time, before their transformation into lethal macrometastatic lesions. Here, we review and discuss progress made in understanding DTC and dormancy biology in breast cancer. Strides in our mechanistic insights of these features has led to the identification of possible targeting strategies, yet, their integration into clinical trial design is still uncertain. Incorporating minimally invasive liquid biopsies and rationally designed adjuvant therapies, targeting both proliferating and dormant tumor cells, may help to address current challenges and improve precision cancer care.
Nature. 2022 Jul;607(7917):156-162. doi: 10.1038/s41586-022-04875-y. Epub 2022 Jun 22. PMID: 35732738.
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An In Vivo CRISPR Screen Identifies Stepwise Genetic Dependencies of Metastatic Progression.
Scheidmann MC, Castro-Giner F, Strittmatter K, Krol I, Paasinen-Sohns A, Scherrer R, Donato C, Gkountela S, Szczerba BM, Diamantopoulou Z, Muenst S, Vlajnic T, Kunz L, Vetter M, Rochlitz C, Taylor V, Giachino C, Schroeder T, Platt RJ, Aceto N.
» Abstract
Blood-borne metastasis of breast cancer involves a series of tightly regulated sequential steps, including the growth of a primary tumor lesion, intravasation of circulating tumor cells (CTC), and adaptation in various distant metastatic sites. The genes orchestrating each of these steps are poorly understood in physiologically relevant contexts, owing to the rarity of experimental models that faithfully recapitulate the biology, growth kinetics, and tropism of human breast cancer. Here, we conducted an in vivo loss-of-function CRISPR screen in newly derived CTC xenografts, unique in their ability to mirror the human disease spontaneously, and identified specific genetic dependencies for each step of the metastatic process. Validation experiments revealed sensitivities to inhibitors that are already available, such as PLK1 inhibitors, to prevent CTC intravasation. Together, these findings present a new tool to reclassify driver genes involved in the spread of human cancer, providing insights into the biology of metastasis and paving the way to test targeted treatment approaches.
Significance: A loss-of-function CRISPR screen in human CTC-derived xenografts identifies genes critical for individual steps of the metastatic cascade, suggesting novel drivers and treatment opportunities for metastatic breast cancers.
Cancer Res. 2022 Feb 15;82(4):681-694. doi: 10.1158/0008-5472.CAN-21-3908. PMID: 34916221; PMCID: PMC7612409.
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In vitro models replicating the human intestinal epithelium for absorption and metabolism studies: A systematic review.
Fedi A, Vitale C, Ponschin G, Ayehunie S, Fato M, Scaglione S.
» Abstract
Absorption, distribution, metabolism and excretion (ADME) studies represent a fundamental step in the early stages of drug discovery. In particular, the absorption of orally administered drugs, which occurs at the intestinal level, has gained attention since poor oral bioavailability often led to failures for new drug approval. In this context, several in vitro preclinical models have been recently developed and optimized to resemble human physiology in the lab better and serve as an animal alternative to accomplish the 3Rs principles. However, numerous models are ineffective in recapitulating the key features of the human small intestine epithelium and lack of prediction potential for drug absorption and metabolism during the preclinical stage.
In this review, we provide an overview of in vitro models aimed at mimicking the intestinal barrier for pharmaceutical screening. After briefly describing how the human small intestine works, we present i) conventional 2D synthetic and cell-based systems, ii) 3D models replicating the main features of the intestinal architecture, iii) micro-physiological systems (MPSs) reproducing the dynamic stimuli to which cells are exposed in the native microenvironment. In this review, we will highlight the benefits and drawbacks of the leading intestinal models used for drug absorption and metabolism studies.
J Control Release. 2021 Jul 10;335:247-268. doi: 10.1016/j.jconrel.2021.05.028. Epub 2021 May 24. PMID: 34033859.
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Fibrin-based factor delivery for therapeutic angiogenesis: friend or foe?
Melly L, Banfi A.
» Abstract
Therapeutic angiogenesis aims at promoting the growth of blood vessels to restore perfusion in ischemic tissues or aid tissue regeneration. Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis in development, repair, and disease. However, exploiting VEGF for therapeutic purposes has been challenging and needs to take into account some key aspects of VEGF biology. In particular, the spatial localization of angiogenic signals within the extracellular matrix is crucial for physiological assembly and function of new blood vessels. Fibrin is the provisional matrix that is universally deposited immediately after injury and supports the initial steps of tissue regeneration. It provides therefore several ideal features as a substrate to promote therapeutic vascularization, especially through its ability to present growth factors in their physiological matrix-bound state and to modulate their availability for signaling. Here, we provide an overview of fibrin uses as a tissue-engineering scaffold material and as a tunable platform to finely control dose and duration of delivery of recombinant factors in therapeutic angiogenesis. However, in some cases, fibrin has also been associated with undesirable outcomes, namely the promotion of fibrosis and scar formation that actually prevent physiological tissue regeneration. Understanding the mechanisms that tip the balance between the pro- and anti-regenerative functions of fibrin will be the key to fully exploit its therapeutic potential.
Cell Tissue Res. 2022 Mar;387(3):451-460. doi: 10.1007/s00441-022-03598-w. Epub 2022 Feb 17. PMID: 35175429; PMCID: PMC8975770.
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Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation.
Kenswil KJG, Pisterzi P, Sánchez-Duffhues G, van Dijk C, Lolli A, Knuth C, Vanchin B, Jaramillo AC, Hoogenboezem RM, Sanders MA, Feyen J, Cupedo T, Costa IG, Li R, Bindels EMJ, Lodder K, Blom B, Bos PK, Goumans MJ, Ten Dijke P, Farrell E, Krenning G, Raaijmakers MHGP.
» Abstract
Bone marrow stromal cells (BMSCs) play pivotal roles in tissue maintenance and regeneration. Their origins, however, remain incompletely understood. Here we identify rare LNGFR+ cells in human fetal and regenerative bone marrow that co-express endothelial and stromal markers. This endothelial subpopulation displays transcriptional reprogramming consistent with endothelial-to-mesenchymal transition (EndoMT) and can generate multipotent stromal cells that reconstitute the bone marrow (BM) niche upon transplantation. Single-cell transcriptomics and lineage tracing in mice confirm robust and sustained contributions of EndoMT to bone precursor and hematopoietic niche pools. Interleukin-33 (IL-33) is overexpressed in subsets of EndoMT cells and drives this conversion process through ST2 receptor signaling. These data reveal generation of tissue-forming BMSCs from mouse and human endothelial cells and may be instructive for approaches to human tissue regeneration.
Cell Stem Cell. 2021 Apr 1;28(4):653-670.e11. doi: 10.1016/j.stem.2021.01.006. Epub 2021 Feb 8. PMID: 33561425
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High blood flow shear stress values are associated with circulating tumor cells cluster disaggregation in a multi-channel microfluidic device.
Marrella A, Fedi A, Varani G, Vaccari I, Fato M, Firpo G, Guida P, Aceto N, Scaglione S.
» Abstract
Metastasis formation is a hallmark of invasive cancers and it is achieved through the shedding of circulating tumor cells (CTCs) from the primary site into the blood circulation. There, CTCs are found as single cells or as multicellular clusters, with clusters carrying an elevated ability to survive within the bloodstream and initiate new metastatic lesions at distant sites. Clusters of CTCs include homotypic clusters made of cancer cells only, as well as heterotypic clusters that incorporate stromal or immune cells along with cancer cells. Both homotypic and heterotypic CTC clusters are characterized by a high metastasis-forming capability, high proliferation rate and by distinct molecular features compared to single CTCs, and their presence in the peripheral circulation of cancer patients is generally associated with a poor prognosis. In this short review, we summarize the current literature that describes homotypic and heterotypic CTC clusters, both in the context of their molecular characteristics as well as their value in the clinical setting. While CTC clusters have only recently emerged as key players in the metastatic process and many aspects of their biology remain to be investigated, a detailed understanding of their vulnerabilities may pave the way towards the generation of new metastasis-suppressing agents.
PLoS One. 2021 Jan 14;16(1):e0245536. doi: 10.1371/journal.pone.0245536.
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Bring along your friends: Homotypic and heterotypic circulating tumor cell clustering to accelerate metastasis.
Aceto N.
» Abstract
Metastasis formation is a hallmark of invasive cancers and it is achieved through the shedding of circulating tumor cells (CTCs) from the primary site into the blood circulation. There, CTCs are found as single cells or as multicellular clusters, with clusters carrying an elevated ability to survive within the bloodstream and initiate new metastatic lesions at distant sites. Clusters of CTCs include homotypic clusters made of cancer cells only, as well as heterotypic clusters that incorporate stromal or immune cells along with cancer cells. Both homotypic and heterotypic CTC clusters are characterized by a high metastasis-forming capability, high proliferation rate and by distinct molecular features compared to single CTCs, and their presence in the peripheral circulation of cancer patients is generally associated with a poor prognosis. In this short review, we summarize the current literature that describes homotypic and heterotypic CTC clusters, both in the context of their molecular characteristics as well as their value in the clinical setting. While CTC clusters have only recently emerged as key players in the metastatic process and many aspects of their biology remain to be investigated, a detailed understanding of their vulnerabilities may pave the way towards the generation of new metastasis-suppressing agents.
Biomed J. 2020 Feb;43(1):18-23. doi: 10.1016/j.bj.2019.11.002. Epub 2020 Feb 11. PMID: 32200952; PMCID: PMC7090281.
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Tracking cancer progression: from circulating tumor cells to metastasis.
Castro-Giner F, Aceto N.
» Abstract
The analysis of circulating tumor cells (CTCs) is an outstanding tool to provide insights into the biology of metastatic cancers, to monitor disease progression, and with potential for use in liquid biopsy-based personalized cancer treatment. These goals are ambitious, yet recent studies are already allowing a sharper understanding of the strengths, challenges, and opportunities provided by liquid biopsy approaches. For instance, through single-cell-resolution genomics and transcriptomics, it is becoming increasingly clear that CTCs are heterogeneous at multiple levels and that only a fraction of them is capable of initiating metastasis. It also appears that CTCs adopt multiple ways to enhance their metastatic potential, including homotypic clustering and heterotypic interactions with immune and stromal cells. On the clinical side, both CTC enumeration and molecular analysis may provide new means to monitor cancer progression and to make individualized treatment decisions, but their use for early cancer detection appears to be challenging compared to that of other tumor derivatives such as circulating tumor DNA. In this review, we summarize current data on CTC biology and CTC-based clinical applications that are likely to impact our understanding of the metastatic process and to influence the clinical management of patients with metastatic cancer, including new prospects that may favor the implementation of precision medicine.
Genome Med. 2020 Mar 19;12(1):31. doi: 10.1186/s13073-020-00728-3. PMID: 32192534; PMCID: PMC7082968.
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Quantification of Protein Secretion from Circulating Tumor Cells in Microfluidic Chambers
Armbrecht L, Rutschmann O, Szczerba BM, Nikoloff J, Aceto N, Dittrich PS.
» Abstract
Cancer cells can be released from a cancerous lesion and migrate into the circulatory system, from whereon they may form metastases at distant sites. Today, it is possible to infer cancer progression and treatment efficacy by determining the number of circulating tumor cells (CTCs) in the patient’s blood at multiple time points; further valuable information about CTC phenotypes remains inaccessible. In this article, a microfluidic method for integrated capture, isolation, and analysis of membrane markers, as well as quantification of proteins secreted by single CTCs and CTC clusters, is introduced. CTCs are isolated from whole blood with extraordinary efficiencies above 95% using dedicated trapping structures that allow co-capture of functionalized magnetic beads to assess protein secretion. The patform is tested with multiple breast cancer cell lines spiked into human blood and mouse-model-derived CTCs. In addition to immunostaining, the secretion level of granulocyte growth-stimulating factor (G-CSF), which is shown to be involved in neutrophil recruitment, is quantified The bead-based assay provides a limit of detection of 1.5 ng mL-1 or less than 3700 molecules per cell. Employing barcoded magnetic beads, this platform can be adapted for multiplexed analysis and can enable comprehensive functional CTC profiling in the future.
Adv Sci (Weinh). 2020 Apr 24;7(11):1903237. doi: 10.1002/advs.201903237.
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Circulating tumor cells: Ready for translation?
Diamantopoulou Z, Castro-Giner F, Aceto N.
» Abstract
Circulating tumor cells (CTCs) are shed from solid cancers in the form of single or clustered cells, and the latter display an extraordinary ability to initiate metastasis. Yet, the biological phenomena that trigger the shedding of CTC clusters from a primary cancerous lesion are poorly understood. Here, when dynamically labeling breast cancer cells along with cancer progression, we observe that the majority of CTC clusters are undergoing hypoxia, while single CTCs are largely normoxic. Strikingly, we find that vascular endothelial growth factor (VEGF) targeting leads to primary tumor shrinkage, but it increases intra-tumor hypoxia, resulting in a higher CTC cluster shedding rate and metastasis formation. Conversely, pro-angiogenic treatment increases primary tumor size, yet it dramatically suppresses the formation of CTC clusters and metastasis. Thus, intra-tumor hypoxia leads to the formation of clustered CTCs with high metastatic ability, and a pro-angiogenic therapy suppresses metastasis formation through the prevention of CTC cluster generation.
J Exp Med. 2020 Aug 3;217(8):e20200356. doi: 10.1084/jem.20200356. PMID: 32644115; PMCID: PMC7398171.
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Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells.
Donato C, Kunz L, Castro-Giner F, Paasinen-Sohns A, Strittmatter K, Szczerba BM, Scherrer R, Di Maggio N, Heusermann W, Biehlmaier O, Beisel C, Vetter M, Rochlitz C, Weber WP, Banfi A, Schroeder T, Aceto N.
» Abstract
Circulating tumor cells (CTCs) are shed from solid cancers in the form of single or clustered cells, and the latter display an extraordinary ability to initiate metastasis. Yet, the biological phenomena that trigger the shedding of CTC clusters from a primary cancerous lesion are poorly understood. Here, when dynamically labeling breast cancer cells along cancer progression, we observe that the majority of CTC clusters are undergoing hypoxia, while single CTCs are largely normoxic. Strikingly, we find that vascular endothelial growth factor (VEGF) targeting leads to primary tumor shrinkage, but it increases intra-tumor hypoxia, resulting in a higher CTC cluster shedding rate and metastasis formation. Conversely, pro-angiogenic treatment increases primary tumor size, yet it dramatically suppresses the formation of CTC clusters and metastasis. Thus, intra-tumor hypoxia leads to the formation of clustered CTCs with high metastatic ability, and a pro-angiogenic therapy suppresses metastasis formation through the prevention of CTC cluster generation.
Cell Rep. 2020 Sep 8;32(10):108105. doi: 10.1016/j.celrep.2020.108105. PMID: 32905777; PMCID: PMC7487783
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Circulating Tumor Cell-Neutrophil Tango along the Metastatic Process.
Saini M, Szczerba BM, Aceto N.
» Abstract
The crosstalk between cancer cells and the immune system is crucial for disease progression and its therapeutic targeting is providing exciting results, in particular with newly developed immune checkpoint inhibitors. Current approaches primarily focus on cellular interactions occurring between tumor cells and T lymphocytes; however, recent data highlight a crucial role of neutrophils in support of tumor progression and suggest yet unexplored treatment opportunities. In this review, we summarize the current understanding of those interactions that occur between neutrophils and cancer cells, focusing on both protumor and antitumor activities of neutrophils at different stages of cancer progression. These include infiltration of neutrophils into the primary tumor, their interactions with circulating tumor cells (CTC) within the bloodstream, and their involvement in the establishment of a metastatic niche. Additionally, we discuss how further investigation of CTCs and their interacting immune cell partners may point towards novel immune checkpoint inhibition strategies and provide new insights on the efficacy of already existing immunotherapies.
Cancer Res. 2019 Dec 15;79(24):6067-6073. doi: 10.1158/0008-5472.CAN-19-1972. Epub 2019 Sep 16. LINK
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To Be Taken in Count: Prostatic Tumor Cells Break Free upon Needle Biopsy.
Saini M, Aceto N.
Clin Chem. 2020 Jan 1;66(1):6-8. doi: 10.1373/clinchem.2019.311696. LINK
Therapeutic vascularization in regenerative medicine.
Gianni-Barrera R, Di Maggio N, Melly L, Burger MG, Mujagic E, Gürke L, Schaefer DJ, Banfi A.
» Abstract
Therapeutic angiogenesis, that is, the generation of new vessels by delivery of specific factors, is required both for rapid vascularization of tissue‐engineered constructs and to treat ischemic conditions. Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis. However, the uncontrolled expression can lead to aberrant vascular growth and vascular tumors (angiomas). Major challenges to fully exploit VEGF potency for therapy include the need to precisely control in vivo distribution of growth factor dose and duration of expression. In fact, the therapeutic window of VEGF delivery depends on its amount in the microenvironment around each producing cell rather than on the total dose, since VEGF remains tightly bound to extracellular matrix (ECM). On the other hand, short‐term expression of less than about 4 weeks leads to unstable vessels, which promptly regress following cessation of the angiogenic stimulus. Here, we will briefly overview some key aspects of the biology of VEGF and angiogenesis and discuss their therapeutic implications with a particular focus on approaches using gene therapy, genetically modified progenitors, and ECM engineering with recombinant factors. Lastly, we will present recent insights into the mechanisms that regulate vessel stabilization and the switch between normal and aberrant vascular growth after VEGF delivery, to identify novel molecular targets that may improve both safety and efficacy of therapeutic angiogenesis.
Stem Cells Transl Med. 2020 Apr;9(4):433-444. doi: 10.1002/sctm.19-0319. Epub 2020 Jan 10. LINK
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3D Perfusable Hydrogel Recapitulating the Cancer Dynamic Environment to in Vitro Investigate Metastatic Colonization.
Vitale C, Fedi A, Marrella A, Varani G, Fato M, Scaglione S.
» Abstract
Despite the great advances that the tissue engineering field has experienced over the last two decades, the amount of in vitro engineered tissues that have reached a stage of a clinical trial is limited. While many challenges are still to be overcome, the lack of vascularization represents a major milestone if tissues bigger than approximately 200 µm are to be transplanted. Cell survival and homeostasis are to a large extent conditioned by the oxygen and nutrient transport (as well as waste removal) by blood vessels on their proximity and spontaneous vascularization in vivo is a relatively slow process, leading all together to necrosis of implanted tissues. Thus, in vitro vascularization appears to be a requirement for the advancement of the field. One of the main approaches to this end is the formation of vascular templates that will develop in vitro together with the targeted engineered tissue. Bioprinting, a fast and reliable method for the deposition of cells and materials in a precise manner, appears like an excellent fabrication technique. In this review, we provide a comprehensive background to the fields of vascularization and bioprinting, providing details on the current strategies, cell sources, materials and outcomes of these studies.
Polymers (Basel). 2020 Oct 24;12(11):E2467. doi: 10.3390/polym12112467. LINK
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Bioprinting Vasculature: Materials, Cells and Emergent Techniques.
Tomasina C, Bodet T, Mota C, Moroni L, Camarero-Espinosa S.
» Abstract
Despite the great advances that the tissue engineering field has experienced over the last two decades, the amount of in vitro engineered tissues that have reached a stage of a clinical trial is limited. While many challenges are still to be overcome, the lack of vascularization represents a major milestone if tissues bigger than approximately 200 µm are to be transplanted. Cell survival and homeostasis are to a large extent conditioned by the oxygen and nutrient transport (as well as waste removal) by blood vessels on their proximity and spontaneous vascularization in vivo is a relatively slow process, leading all together to necrosis of implanted tissues. Thus, in vitro vascularization appears to be a requirement for the advancement of the field. One of the main approaches to this end is the formation of vascular templates that will develop in vitro together with the targeted engineered tissue. Bioprinting, a fast and reliable method for the deposition of cells and materials in a precise manner, appears like an excellent fabrication technique. In this review, we provide a comprehensive background to the fields of vascularization and bioprinting, providing details on the current strategies, cell sources, materials, and outcomes of these studies.
Materials (Basel). 2019 Aug 23;12(17):2701. doi: 10.3390/ma12172701. LINK
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Cancer Diagnosis Using a Liquid Biopsy: Challenges and Expectations.
Castro-Giner F, Gkountela S, Donato C, Alborelli I, Quagliata L, Ng CKY, Piscuoglio S, Aceto N
» Abstract
The field of cancer diagnostics has recently been impacted by new and exciting developments in the area of liquid biopsy. A liquid biopsy is a minimally invasive alternative to surgical biopsies of solid tissues, typically achieved through the withdrawal of a blood sample or other body fluids, allowing the interrogation of tumor-derived material including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) fragments that are present at a given time point. In this short review, we discuss a few studies that summarize the state-of-the-art in the liquid biopsy field from a diagnostic perspective and speculate on current challenges and expectations of implementing liquid biopsy testing for cancer diagnosis and monitoring in the clinical setting.
Diagnostics (Basel). 2018 May 9;8(2):31. doi: 10.3390/diagnostics8020031LINK
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