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Cells
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Micro- and Macro-Environmental Factors in Solid Cancers
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Micro- and Macro-Environmental Factors in Solid Cancers

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 20939

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Elda Tagliabue

E-Mail Website1 Website2
Guest Editor
Head of Molecular Targeting Unit, Department of Research, AmadeoLab, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy
Interests: HER2-positive breast cancer; triple-negative breast cancer; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Although cancer development and progression depend on stochastic mutational events, active cross-talk between cancer cells and the normal cells surrounding them is essential in supporting tumor progression.

Cells adjacent to tumors rapidly acquire characteristics that render them able to sustain tumor progression and resistance to treatment. Cancer-associated fibroblasts take part in tumorigenesis by creating an environment permissive to tumor proliferation and invasiveness. Similarly, in several different solid cancers, adipocytes modify their phenotype to decrease the expression of differentiation markers and lipid content and participate in the acquisition of an aggressive tumor phenotype.

The formation of new blood vessels, which is essential to supply oxygen and nutrients to the tumor and to provide a gateway for metastasis, is regulated by the balance between angiogenic activators and inhibitors within the tumor microenvironment.

During tumor progression, tumor cell variants resulting from immune selection promote a pro-tumor immune milieu other than facilitating the escape from immune attack.

Besides an abnormal organ composed of multiple cell types, which contributes to its malignancy, the tumor has to be seen in the context of the host environment. The development and progression of malignant cells are strictly dependent on reprogramming of the cellular metabolism to fulfill the biosynthetic demands associated with proliferation. Host metabolic and gut microbiota characteristics regulate energy storage and inflammation levels and are in turn dependent on lifestyle. 

Understanding the micro- and macro-environmental factors that support solid tumors is at the root of cancer prevention and cure.

In this Special Issue of Cells, we invite your contributions, either in the form of original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “Micro- and macro-environmental factors in solid cancers.

 Relevant topics include, but are not limited to

  • Cancer-associeted fibroblasts: their characteristics, function and interplay with tumors
  • Cancer-associeted adipocytes: their characteristics, function and interplay with tumors
  • Interaction of the extracellular matrix, stoma and tumor cells
  • Tumor angiogenesis
  • Tumor-infiltrating immune cells: their characteristics, function and interplay with tumors
  • Tumor metabolism
  •  Bi-directional interplay between tumor and host (e.g. obesity, BMI, lifestyle cachexia)
  • Commensal bacteria and tumor

Dr. Elda Tagliabue
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • stromal cells
  • immune cells
  • angiogenesis
  • metabolism
  • commensal bacteria
  • obesity
  • BMI
  • lifestyle
  • cachexia

Published Papers (6 papers)

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Editorial

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4 pages, 186 KiB  
Editorial
Special Issue: Micro- and Macro-Environmental Factors in Solid Cancers
by Elda Tagliabue
Cells 2021, 10(2), 247; https://doi.org/10.3390/cells10020247 - 27 Jan 2021
Viewed by 1656
Abstract
Paracrine and endocrine signaling between the tumor and host have been convincingly shown to support tumor progression [...] Full article
(This article belongs to the Special Issue Micro- and Macro-Environmental Factors in Solid Cancers)

Research

Jump to: Editorial, Review

15 pages, 1879 KiB  
Article
miR-9-Mediated Inhibition of EFEMP1 Contributes to the Acquisition of Pro-Tumoral Properties in Normal Fibroblasts
by Giulia Cosentino, Sandra Romero-Cordoba, Ilaria Plantamura, Alessandra Cataldo and Marilena V. Iorio
Cells 2020, 9(9), 2143; https://doi.org/10.3390/cells9092143 - 22 Sep 2020
Cited by 15 | Viewed by 2718
Abstract
Tumor growth and invasion occurs through a dynamic interaction between cancer and stromal cells, which support an aggressive niche. MicroRNAs are thought to act as tumor messengers to “corrupt” stromal cells. We previously demonstrated that miR-9, a known metastamiR, is released by triple [...] Read more.
Tumor growth and invasion occurs through a dynamic interaction between cancer and stromal cells, which support an aggressive niche. MicroRNAs are thought to act as tumor messengers to “corrupt” stromal cells. We previously demonstrated that miR-9, a known metastamiR, is released by triple negative breast cancer (TNBC) cells to enhance the transition of normal fibroblasts (NFs) into cancer-associated fibroblast (CAF)-like cells. EGF containing fibulin extracellular matrix protein 1 (EFEMP1), which encodes for the ECM glycoprotein fibulin-3, emerged as a miR-9 putative target upon miRNA’s exogenous upmodulation in NFs. Here we explored the impact of EFEMP1 downmodulation on fibroblast’s acquisition of CAF-like features, and how this phenotype influences neoplastic cells to gain chemoresistance. Indeed, upon miR-9 overexpression in NFs, EFEMP1 resulted downmodulated, both at RNA and protein levels. The luciferase reporter assay showed that miR-9 directly targets EFEMP1 and its silencing recapitulates miR-9-induced pro-tumoral phenotype in fibroblasts. In particular, EFEMP1 siRNA-transfected (si-EFEMP1) fibroblasts have an increased ability to migrate and invade. Moreover, TNBC cells conditioned with the supernatant of NFs transfected with miR-9 or si-EFEMP1 became more resistant to cisplatin. Overall, our results demonstrate that miR-9/EFEMP1 axis is crucial for the conversion of NFs to CAF-like cells under TNBC signaling. Full article
(This article belongs to the Special Issue Micro- and Macro-Environmental Factors in Solid Cancers)
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14 pages, 2184 KiB  
Article
CCN-Based Therapeutic Peptides Modify Pancreatic Ductal Adenocarcinoma Microenvironment and Decrease Tumor Growth in Combination with Chemotherapy
by Andrea Resovi, Patrizia Borsotti, Tommaso Ceruti, Alice Passoni, Massimo Zucchetti, Alexander Berndt, Bruce L. Riser, Giulia Taraboletti and Dorina Belotti
Cells 2020, 9(4), 952; https://doi.org/10.3390/cells9040952 - 13 Apr 2020
Cited by 19 | Viewed by 3488
Abstract
The prominent desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a determinant factor in tumor progression and a major barrier to the access of chemotherapy. The PDAC microenvironment therefore appears to be a promising therapeutic target. CCN2/CTGF is a profibrotic matricellular protein, highly [...] Read more.
The prominent desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a determinant factor in tumor progression and a major barrier to the access of chemotherapy. The PDAC microenvironment therefore appears to be a promising therapeutic target. CCN2/CTGF is a profibrotic matricellular protein, highly present in the PDAC microenvironment and associated with disease progression. Here we have investigated the therapeutic value of the CCN2-targeting BLR100 and BLR200, two modified synthetic peptides derived from active regions of CCN3, an endogenous inhibitor of CCN2. In a murine orthotopic PDAC model, the two peptides, administered as monotherapy at low doses (approximating physiological levels of CCN3), had tumor inhibitory activity that increased with the dose. The peptides affected the tumor microenvironment, inhibiting fibrosis and vessel formation and reducing necrosis. Both peptides were active in preventing ascites formation. An increased activity was obtained in combination regimens, administering BLR100 or BLR200 with the chemotherapeutic drug gemcitabine. Pharmacokinetic analysis indicated that the improved activity of the combination was not mainly determined by the substantial increase in gemcitabine delivery to tumors, suggesting other effects on the tumor microenvironment. The beneficial remodeling of the tumor stroma supports the potential value of these CCN3-derived peptides for targeting pathways regulated by CCN2 in PDAC. Full article
(This article belongs to the Special Issue Micro- and Macro-Environmental Factors in Solid Cancers)
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16 pages, 3091 KiB  
Article
Evaluation of Glycosylated PTGS2 in Colorectal Cancer for NSAIDS-Based Adjuvant Therapy
by Roberta Venè, Delfina Costa, Raffaella Augugliaro, Sebastiano Carlone, Stefano Scabini, Gianmaria Casoni Pattacini, Maurizio Boggio, Simonetta Zupo, Federica Grillo, Luca Mastracci, Francesca Pitto, Simona Minghelli, Nicoletta Ferrari, Francesca Tosetti, Emanuele Romairone, Maria C. Mingari, Alessandro Poggi and Roberto Benelli
Cells 2020, 9(3), 683; https://doi.org/10.3390/cells9030683 - 11 Mar 2020
Cited by 11 | Viewed by 3286
Abstract
Observational/retrospective studies indicate that prostaglandin-endoperoxide synthase-2 (PTGS2) inhibitors could positively affect colorectal cancer (CRC) patients’ survival after diagnosis. To obtain an acceptable cost/benefit balance, the inclusion of PTGS2 inhibitors in the adjuvant setting needs a selective criterion. We quantified the 72 kDa, CRC-associated, [...] Read more.
Observational/retrospective studies indicate that prostaglandin-endoperoxide synthase-2 (PTGS2) inhibitors could positively affect colorectal cancer (CRC) patients’ survival after diagnosis. To obtain an acceptable cost/benefit balance, the inclusion of PTGS2 inhibitors in the adjuvant setting needs a selective criterion. We quantified the 72 kDa, CRC-associated, glycosylated form of PTGS2 in 100 frozen CRC specimens and evaluated PTGS2 localization by IHC in the same tumors, scoring tumor epithelial-derived and stroma-derived fractions. We also investigated the involvement of interleukin-1 beta (IL1β) in PTGS2 induction, both in vitro and in CRC lysates. Finally, we used overall survival (OS) as a criterion for patient selection. Glycosylated PTGS2 can be quantified with high sensibility in tissue lysates, but the expression in both tumor and stromal cells limits its use for predictive purposes. Immunohistochemistry (IHC) analysis indicates that stromal PTGS2 expression could exert a protective role on patient OS. Stromal PTGS2 was prevalently expressed by cancer-associated fibroblasts exerting a barrier function near the gut lumen, and it apparently favored the antitumor M1 macrophage population. IL1β was directly linked to gPTGS2 expression both in vitro and in tumors, but its activity was apparently prevalent on the stromal cell population. We suggest that stromal PTGS2 could exert a positive effect on patients OS when expressed in the luminal area of the tumor. Full article
(This article belongs to the Special Issue Micro- and Macro-Environmental Factors in Solid Cancers)
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Review

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15 pages, 1371 KiB  
Review
Cancer Stem Cells: Devil or Savior—Looking behind the Scenes of Immunotherapy Failure
by Lorenzo Castagnoli, Francesca De Santis, Tatiana Volpari, Claudio Vernieri, Elda Tagliabue, Massimo Di Nicola and Serenella M. Pupa
Cells 2020, 9(3), 555; https://doi.org/10.3390/cells9030555 - 27 Feb 2020
Cited by 24 | Viewed by 3919
Abstract
Although the introduction of immunotherapy has tremendously improved the prognosis of patients with metastatic cancers of different histological origins, some tumors fail to respond or develop resistance. Broadening the clinical efficacy of currently available immunotherapy strategies requires an improved understanding of the biological [...] Read more.
Although the introduction of immunotherapy has tremendously improved the prognosis of patients with metastatic cancers of different histological origins, some tumors fail to respond or develop resistance. Broadening the clinical efficacy of currently available immunotherapy strategies requires an improved understanding of the biological mechanisms underlying cancer immune escape. Globally, tumor cells evade immune attack using two main strategies: avoiding recognition by immune cells and instigating an immunosuppressive tumor microenvironment. Emerging data suggest that the clinical efficacy of chemotherapy or molecularly targeted therapy is related to the ability of these therapies to target cancer stem cells (CSCs). However, little is known about the role of CSCs in mediating tumor resistance to immunotherapy. Due to their immunomodulating features and plasticity, CSCs can be especially proficient at evading immune surveillance, thus potentially representing the most prominent malignant cell component implicated in primary or acquired resistance to immunotherapy. The identification of immunomodulatory properties of CSCs that include mechanisms that regulate their interactions with immune cells, such as bidirectional release of particular cytokines/chemokines, fusion of CSCs with fusogenic stromal cells, and cell-to-cell communication exerted by extracellular vesicles, may significantly improve the efficacy of current immunotherapy strategies. The purpose of this review is to discuss the current scientific evidence linking CSC biological, immunological, and epigenetic features to tumor resistance to immunotherapy. Full article
(This article belongs to the Special Issue Micro- and Macro-Environmental Factors in Solid Cancers)
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22 pages, 1040 KiB  
Review
Esophageal Cancer Development: Crucial Clues Arising from the Extracellular Matrix
by Antonio Palumbo, Jr., Nathalia Meireles Da Costa, Bruno Pontes, Felipe Leite de Oliveira, Matheus Lohan Codeço, Luis Felipe Ribeiro Pinto and Luiz Eurico Nasciutti
Cells 2020, 9(2), 455; https://doi.org/10.3390/cells9020455 - 17 Feb 2020
Cited by 36 | Viewed by 4984
Abstract
In the last years, the extracellular matrix (ECM) has been reported as playing a relevant role in esophageal cancer (EC) development, with this compartment being related to several aspects of EC genesis and progression. This sounds very interesting due to the complexity of [...] Read more.
In the last years, the extracellular matrix (ECM) has been reported as playing a relevant role in esophageal cancer (EC) development, with this compartment being related to several aspects of EC genesis and progression. This sounds very interesting due to the complexity of this highly incident and lethal tumor, which takes the sixth position in mortality among all tumor types worldwide. The well-established increase in ECM stiffness, which is able to trigger mechanotransduction signaling, is capable of regulating several malignant behaviors by converting alteration in ECM mechanics into cytoplasmatic biochemical signals. In this sense, it has been shown that some molecules play a key role in these events, particularly the different collagen isoforms, as well as enzymes related to its turnover, such as lysyl oxidase (LOX) and matrix metalloproteinases (MMPs). In fact, MMPs are not only involved in ECM stiffness, but also in other events related to ECM homeostasis, which includes ECM remodeling. Therefore, the crucial role of distinct MMPs isoform has already been reported, especially MMP-2, -3, -7, and -9, along EC development, thus strongly associating these proteins with the control of important cellular events during tumor progression, particularly in the process of invasion during metastasis establishment. In addition, by distinct mechanisms, a vast diversity of glycoproteins and proteoglycans, such as laminin, fibronectin, tenascin C, galectin, dermatan sulfate, and hyaluronic acid exert remarkable effects in esophageal malignant cells due to the activation of oncogenic signaling pathways mainly involved in cytoskeleton alterations during adhesion and migration processes. Finally, the wide spectrum of interactions potentially mediated by ECM may represent a singular intervention scenario in esophageal carcinogenesis natural history and, due to the scarce knowledge on the cellular and molecular mechanisms involved in EC development, the growing body of evidence on ECM’s role along esophageal carcinogenesis might provide a solid base to improve its management in the future. Full article
(This article belongs to the Special Issue Micro- and Macro-Environmental Factors in Solid Cancers)
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