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A Special Issue on Tumor Stroma...
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A Special Issue on Tumor Stroma

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 99112

Special Issue Editors

Dr. Hossein Tavana

E-Mail Website
Guest Editor
The University of Akron, Akron, OH 44325, USA
Interests: Tumor modeling; Tumor microenvironment; Drug resistance
Dr. Luis Solorio

E-Mail Website
Guest Editor
Assistant Professor, Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA
Interests: tumor microenvironment; cancer models; 3D cultures; drug resistance; fibrin; fibronectin
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Our evolving understanding of cancer indicates that the tumor stroma is a dynamic environment that plays significant roles in tumor growth, drug resistance, and cancer cell invasion and metastasis. Tumor stroma undergoes biochemical and physical alterations in the protein composition, matrix protein architecture, and tissue mechanical properties that collectively accommodate the emerging needs of cancer cells during different stages of the disease. The stromal cells including fibroblast cells, vascular cells, and immune cells also act in concert to regulate a broad range of functions of cancer cells and their resistance to therapeutics. This special issue will report both recent developments and expert opinion on our understanding of tumor stroma as a driver of the disease as well as its potential as a therapeutic target. We welcome submissions that use different approaches such as three-dimensional cell cultures, organoids, and/or animal models to study the role of specific stromal cells and the extracellular matrix on phenotypic and functional regulation of solid cancers and elucidate underlying molecular mechanisms.

Dr. Hossein Tavana
Dr. Luis Solorio
Guest Editors

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. Cancers 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 2900 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.

Published Papers (20 papers)

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16 pages, 2176 KiB  
Article
A 3D Heterotypic Breast Cancer Model Demonstrates a Role for Mesenchymal Stem Cells in Driving a Proliferative and Invasive Phenotype
by Amarnath Pal, Jennifer C. Ashworth, Pamela Collier, Catherine Probert, Sal Jones, Eduardo Pernaut Leza, Marian L. Meakin, Alison A. Ritchie, David Onion, Philip A Clarke, Cinzia Allegrucci and Anna M. Grabowska
Cancers 2020, 12(8), 2290; https://doi.org/10.3390/cancers12082290 - 14 Aug 2020
Cited by 9 | Viewed by 3912
Abstract
Previous indirect 2D co-culture studies have demonstrated that mesenchymal stem cells (MSCs) promote breast cancer (BC) progression through secretion of paracrine factors including growth factors, cytokines and chemokines. In order to investigate this aspect of the tumour microenvironment in a more relevant 3D [...] Read more.
Previous indirect 2D co-culture studies have demonstrated that mesenchymal stem cells (MSCs) promote breast cancer (BC) progression through secretion of paracrine factors including growth factors, cytokines and chemokines. In order to investigate this aspect of the tumour microenvironment in a more relevant 3D co-culture model, spheroids incorporating breast cancer cells (BCCs), both cell lines and primary BCCs expanded as patient-derived xenografts, and MSCs were established. MSCs in co-cultures were shown to enhance proliferation of estrogen receptor (ER)/progesterone receptor (PR)-positive BCCs. In addition, co-culture resulted in downregulation of E-cadherin in parallel with upregulation of the epithelial-mesenchymal transition (EMT)-relation transcription factor, SNAIL. Cytoplasmic relocalization of ski-related novel protein N (SnON), a negative regulator of transforming growth factor-beta (TGF-β) signalling, and of β-catenin, involved in a number of pathways including Wnt signalling, was also observed in BCCs in co-cultures in contrast to monocultures. In addition, the β-catenin inhibitor, 3-[[(4-methylphenyl)sulfonyl]amino]-benzoic acid methyl ester (MSAB), mediated reduced growth and invasion in the co-cultures. This study highlights the potential role for SnON as a biomarker for BC invasiveness, and the importance of interactions between TGF-β and Wnt signalling, involving SnON. Such pathways may contribute towards identifying possible targets for therapeutic intervention in BC patients. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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19 pages, 5644 KiB  
Article
Knockdown of Leptin Receptor Affects Macrophage Phenotype in the Tumor Microenvironment Inhibiting Breast Cancer Growth and Progression
by Luca Gelsomino, Giuseppina Daniela Naimo, Rocco Malivindi, Giuseppina Augimeri, Salvatore Panza, Cinzia Giordano, Ines Barone, Daniela Bonofiglio, Loredana Mauro, Stefania Catalano and Sebastiano Andò
Cancers 2020, 12(8), 2078; https://doi.org/10.3390/cancers12082078 - 27 Jul 2020
Cited by 20 | Viewed by 3425
Abstract
Aberrant leptin (Ob) signaling, a hallmark of obesity, has been recognized to influence breast cancer (BC) biology within the tumor microenvironment (TME). Here, we evaluated the impact of leptin receptor (ObR) knockdown in affecting BC phenotype and in mediating the interaction between tumor [...] Read more.
Aberrant leptin (Ob) signaling, a hallmark of obesity, has been recognized to influence breast cancer (BC) biology within the tumor microenvironment (TME). Here, we evaluated the impact of leptin receptor (ObR) knockdown in affecting BC phenotype and in mediating the interaction between tumor cells and macrophages, the most abundant immune cells within the TME. The stable knockdown of ObR (ObR sh) in ERα-positive and ERα-negative BC cells turned the tumor phenotype into a less aggressive one, as evidenced by in vitro and in vivo models. In xenograft tumors and in co-culture experiments between circulating monocytes and BC cells, the absence of ObR reduced the recruitment of macrophages, and also affected their cytokine mRNA expression profile. This was associated with a decreased expression and secretion of monocyte chemoattractant protein-1 in ObR sh clones. The loss of Ob/ObR signaling modulated the immunosuppressive TME, as shown by a reduced expression of programmed death ligand 1/programmed cell death protein 1/arginase 1. In addition, we observed increased phagocytic activity of macrophages compared to control Sh clones in the presence of ObR sh-derived conditioned medium. Our findings, addressing an innovative role of ObR in modulating immune TME, may open new avenues to improve BC patient health care. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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17 pages, 3399 KiB  
Article
Prognostic Value of CXCR2 in Breast Cancer
by Florence Boissière-Michot, William Jacot, Julien Fraisse, Sophie Gourgou, Colin Timaxian and Gwendal Lazennec
Cancers 2020, 12(8), 2076; https://doi.org/10.3390/cancers12082076 - 27 Jul 2020
Cited by 18 | Viewed by 2769
Abstract
The tumor microenvironment appears essential in cancer progression and chemokines are mediators of the communication between cancer cells and stromal cells. We have previously shown that the ligands of the chemokine receptor CXCR2 were expressed at higher levels in triple-negative breast cancers (TNBC). [...] Read more.
The tumor microenvironment appears essential in cancer progression and chemokines are mediators of the communication between cancer cells and stromal cells. We have previously shown that the ligands of the chemokine receptor CXCR2 were expressed at higher levels in triple-negative breast cancers (TNBC). Our hypothesis was that CXCR2 expression could also be altered in breast cancer. Here, we have analyzed the potential role of CXCR2 in breast cancer in a retrospective cohort of 105 breast cancer patients. Expression of CXCR2, CD11b (a marker of granulocytes) and CD66b (a marker of neutrophils) was analyzed by immunohistochemistry on tumor samples. We demonstrated that CXCR2 stained mainly stromal cells and in particular neutrophils. CXCR2, CD11b and CD66b expression were correlated with high grade breast cancers. Moreover, TNBC displayed a higher expression of CXCR2, CD11b and CD66b than hormone receptor positive or Her2 positive tumors. High levels of CXCR2 and CD11b, but not CD66b, were associated with a higher infiltration of T lymphocytes and B lymphocytes. We also observed a correlation between CXCR2 and AP-1 activity. In univariate analyses, CXCR2, but not CD11b or CD66b, was associated with a lower risk of relapse; CXCR2 remained significant in multivariate analysis. Our data suggest that CXCR2 is a stromal marker of TNBC. However, higher levels of CXCR2 predicted a lower risk of relapse. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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17 pages, 5527 KiB  
Article
Diffusion Kurtosis Imaging—A Superior Approach to Assess Tumor–Stroma Ratio in Pancreatic Ductal Adenocarcinoma
by Philipp Mayer, Yixin Jiang, Tristan A. Kuder, Frank Bergmann, Ekaterina Khristenko, Verena Steinle, Jörg Kaiser, Thilo Hackert, Hans-Ulrich Kauczor, Miriam Klauß and Matthias M. Gaida
Cancers 2020, 12(6), 1656; https://doi.org/10.3390/cancers12061656 - 22 Jun 2020
Cited by 13 | Viewed by 3050
Abstract
Extensive desmoplastic stroma is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to tumor progression and to the relative resistance of tumor cells towards (radio) chemotherapy. Thus, therapies that target the stroma are under intense investigation. To allow the stratification of patients [...] Read more.
Extensive desmoplastic stroma is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to tumor progression and to the relative resistance of tumor cells towards (radio) chemotherapy. Thus, therapies that target the stroma are under intense investigation. To allow the stratification of patients who would profit from such therapies, non-invasive methods assessing the stroma content in relation to tumor mass are required. In the current prospective study, we investigated the usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI), a radiologic method that measures the random motion of water molecules in tissue, in the assessment of PDAC lesions, and more specifically in the desmoplastic tumor stroma. We made use of a sophisticated DW-MRI approach, the so-called diffusion kurtosis imaging (DKI), which possesses potential advantages over conventional and widely used monoexponential diffusion-weighted imaging analysis (cDWI). We found that the diffusion constant D from DKI is highly negatively correlated with the percentage of tumor stroma, the latter determined by histology. D performed significantly better than the widely used apparent diffusion coefficient (ADC) from cDWI in distinguishing stroma-rich (>50% stroma percentage) from stroma-poor tumors (≤50% stroma percentage). Moreover, we could prove the potential of the diffusion constant D as a clinically useful imaging parameter for the differentiation of PDAC-lesions from non-neoplastic pancreatic parenchyma. Therefore, the diffusion constant D from DKI could represent a valuable non-invasive imaging biomarker for assessment of stroma content in PDAC, which is applicable for the clinical diagnostic of PDAC. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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13 pages, 3443 KiB  
Article
Improved Outcome Prediction for Appendiceal Pseudomyxoma Peritonei by Integration of Cancer Cell and Stromal Transcriptional Profiles
by Claudio Isella, Marco Vaira, Manuela Robella, Sara Erika Bellomo, Gabriele Picco, Alice Borsano, Andrea Mignone, Consalvo Petti, Roberta Porporato, Alexandra Ambra Ulla, Alberto Pisacane, Anna Sapino, Michele De Simone and Enzo Medico
Cancers 2020, 12(6), 1495; https://doi.org/10.3390/cancers12061495 - 08 Jun 2020
Cited by 5 | Viewed by 2872
Abstract
In recent years, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have substantially improved the clinical outcome of pseudomyxoma peritonei (PMP) originating from mucinous appendiceal cancer. However, current histopathological grading of appendiceal PMP frequently fails in predicting disease outcome. We recently observed that [...] Read more.
In recent years, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have substantially improved the clinical outcome of pseudomyxoma peritonei (PMP) originating from mucinous appendiceal cancer. However, current histopathological grading of appendiceal PMP frequently fails in predicting disease outcome. We recently observed that the integration of cancer cell transcriptional traits with those of cancer-associated fibroblasts (CAFs) improves prognostic prediction for tumors of the large intestine. We therefore generated global expression profiles on a consecutive series of 24 PMP patients treated with CRS plus HIPEC. Multiple lesions were profiled for nine patients. We then used expression data to stratify the samples by a previously published “high-risk appendiceal cancer” (HRAC) signature and by a CAF signature that we previously developed for colorectal cancer, or by a combination of both. The prognostic value of the HRAC signature was confirmed in our cohort and further improved by integration of the CAF signature. Classification of cases profiled for multiple lesions revealed the existence of outlier samples and highlighted the need of profiling multiple PMP lesions to select representative samples for optimal performances. The integrated predictor was subsequently validated in an independent PMP cohort. These results provide new insights into PMP biology, revealing a previously unrecognized prognostic role of the stromal component and supporting integration of standard pathological grade with the HRAC and CAF transcriptional signatures to better predict disease outcome. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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19 pages, 4877 KiB  
Article
Role of Collagen Fiber Morphology on Ovarian Cancer Cell Migration Using Image-Based Models of the Extracellular Matrix
by Samuel Alkmin, Rebecca Brodziski, Haleigh Simon, Daniel Hinton, Randall H. Goldsmith, Manish Patankar and Paul J. Campagnola
Cancers 2020, 12(6), 1390; https://doi.org/10.3390/cancers12061390 - 28 May 2020
Cited by 26 | Viewed by 4388
Abstract
Remodeling of the extracellular matrix (ECM) is an important part in the development and progression of many epithelial cancers. However, the biological significance of collagen alterations in ovarian cancer has not been well established. Here we investigated the role of collagen fiber morphology [...] Read more.
Remodeling of the extracellular matrix (ECM) is an important part in the development and progression of many epithelial cancers. However, the biological significance of collagen alterations in ovarian cancer has not been well established. Here we investigated the role of collagen fiber morphology on cancer cell migration using tissue engineered scaffolds based on high-resolution Second-Harmonic Generation (SHG) images of ovarian tumors. The collagen-based scaffolds are fabricated by multiphoton excited (MPE) polymerization, which is a freeform 3D method affording submicron resolution feature sizes (~0.5 µm). This capability allows the replication of the collagen fiber architecture, where we constructed models representing normal stroma, high-risk tissue, benign tumors, and high-grade tumors. These were seeded with normal and ovarian cancer cell lines to investigate the separate roles of the cell type and matrix morphology on migration dynamics. The primary finding is that key cell–matrix interactions such as motility, cell spreading, f-actin alignment, focal adhesion, and cadherin expression are mainly determined by the collagen fiber morphology to a larger extent than the initial cell type. Moreover, we found these aspects were all enhanced for cells on the highly aligned, high-grade tumor model. Conversely, the weakest corresponding responses were observed on the more random mesh-like normal stromal matrix, with the partially aligned benign tumor and high-risk models demonstrating intermediate behavior. These results are all consistent with a contact guidance mechanism. These models cannot be synthesized by other conventional fabrication methods, and we suggest this approach will enable a variety of studies in cancer biology. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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23 pages, 5731 KiB  
Article
Tumor Cell Associated Hyaluronan-CD44 Signaling Promotes Pro-Tumor Inflammation in Breast Cancer
by Patrice M. Witschen, Thomas S. Chaffee, Nicholas J. Brady, Danielle N. Huggins, Todd P. Knutson, Rebecca S. LaRue, Sarah A. Munro, Lyubov Tiegs, James B. McCarthy, Andrew C. Nelson and Kathryn L. Schwertfeger
Cancers 2020, 12(5), 1325; https://doi.org/10.3390/cancers12051325 - 22 May 2020
Cited by 19 | Viewed by 4842
Abstract
Cancer has been conceptualized as a chronic wound with a predominance of tumor promoting inflammation. Given the accumulating evidence that the microenvironment supports tumor growth, we investigated hyaluronan (HA)-CD44 interactions within breast cancer cells, to determine whether this axis directly impacts the formation [...] Read more.
Cancer has been conceptualized as a chronic wound with a predominance of tumor promoting inflammation. Given the accumulating evidence that the microenvironment supports tumor growth, we investigated hyaluronan (HA)-CD44 interactions within breast cancer cells, to determine whether this axis directly impacts the formation of an inflammatory microenvironment. Our results demonstrate that breast cancer cells synthesize and fragment HA and express CD44 on the cell surface. Using RNA sequencing approaches, we found that loss of CD44 in breast cancer cells altered the expression of cytokine-related genes. Specifically, we found that production of the chemokine CCL2 by breast cancer cells was significantly decreased after depletion of either CD44 or HA. In vivo, we found that CD44 deletion in breast cancer cells resulted in a delay in tumor formation and localized progression. This finding was accompanied by a decrease in infiltrating CD206+ macrophages, which are typically associated with tumor promoting functions. Importantly, our laboratory results were supported by human breast cancer patient data, where increased HAS2 expression was significantly associated with a tumor promoting inflammatory gene signature. Because high levels of HA deposition within many tumor types yields a poorer prognosis, our results emphasize that HA-CD44 interactions potentially have broad implications across multiple cancers. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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20 pages, 3732 KiB  
Article
The Dynamic Relationship of Breast Cancer Cells and Fibroblasts in Fibronectin Accumulation at Primary and Metastatic Tumor Sites
by Sarah Libring, Aparna Shinde, Monica K. Chanda, Maryam Nuru, Heather George, Aya M. Saleh, Ammara Abdullah, Tamara L. Kinzer-Ursem, Sarah Calve, Michael K. Wendt and Luis Solorio
Cancers 2020, 12(5), 1270; https://doi.org/10.3390/cancers12051270 - 17 May 2020
Cited by 67 | Viewed by 8085
Abstract
In breast cancer (BC), tissue stiffening via fibronectin (FN) and collagen accumulation is associated with advanced disease progression at both the primary tumor and metastatic sites. Here, we evaluate FN production in 15 BC cell lines, representing a variety of subtypes, phenotypes, metastatic [...] Read more.
In breast cancer (BC), tissue stiffening via fibronectin (FN) and collagen accumulation is associated with advanced disease progression at both the primary tumor and metastatic sites. Here, we evaluate FN production in 15 BC cell lines, representing a variety of subtypes, phenotypes, metastatic potentials, and chemotherapeutic sensitivities. We demonstrate that intracellular and soluble FN is initially lost during tumorigenic transformation but is rescued in all lines with epithelial-mesenchymal plasticity (EMP). Importantly, we establish that no BC cell line was able to independently organize a robust FN matrix. Non-transformed mammary epithelial cells were also unable to deposit FN matrices unless transglutaminase 2, a FN crosslinking enzyme, was overexpressed. Instead, BC cells manipulated the FN matrix production of fibroblasts in a phenotypic-dependent manner. In addition, varied accumulation levels were seen depending if the fibroblasts were conditioned to model paracrine signaling or endocrine signaling of the metastatic niche. In the former, fibroblasts conditioned by BC cultures with high EMP resulted in the largest FN matrix accumulation. In contrast, mesenchymal BC cells produced extracellular vesicles (EV) that resulted in the highest levels of matrix formation by conditioned fibroblasts. Overall, we demonstrate a dynamic relationship between tumor and stromal cells within the tumor microenvironment, in which the levels and fibrillarization of FN in the extracellular matrix are modulated during the particular stages of disease progression. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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19 pages, 5294 KiB  
Article
Breast Fibroblasts and ECM Components Modulate Breast Cancer Cell Migration through the Secretion of MMPs in a 3D Microfluidic Co-Culture Model
by Karina M. Lugo-Cintrón, Max M. Gong, José M. Ayuso, Lucas A. Tomko, David J. Beebe, María Virumbrales-Muñoz and Suzanne M. Ponik
Cancers 2020, 12(5), 1173; https://doi.org/10.3390/cancers12051173 - 06 May 2020
Cited by 53 | Viewed by 6329
Abstract
The extracellular matrix (ECM) composition greatly influences cancer progression, leading to differential invasion, migration, and metastatic potential. In breast cancer, ECM components, such as fibroblasts and ECM proteins, have the potential to alter cancer cell migration. However, the lack of in vitro migration [...] Read more.
The extracellular matrix (ECM) composition greatly influences cancer progression, leading to differential invasion, migration, and metastatic potential. In breast cancer, ECM components, such as fibroblasts and ECM proteins, have the potential to alter cancer cell migration. However, the lack of in vitro migration models that can vary ECM composition limits our knowledge of how specific ECM components contribute to cancer progression. Here, a microfluidic model was used to study the effect of 3D heterogeneous ECMs (i.e., fibroblasts and different ECM protein compositions) on the migration distance of a highly invasive human breast cancer cell line, MDA-MB-231. Specifically, we show that in the presence of normal breast fibroblasts, a fibronectin-rich matrix induces more cancer cell migration. Analysis of the ECM revealed the presence of ECM tunnels. Likewise, cancer-stromal crosstalk induced an increase in the secretion of metalloproteinases (MMPs) in co-cultures. When MMPs were inhibited, migration distance decreased in all conditions except for the fibronectin-rich matrix in the co-culture with human mammary fibroblasts (HMFs). This model mimics the in vivo invasion microenvironment, allowing the examination of cancer cell migration in a relevant context. In general, this data demonstrates the capability of the model to pinpoint the contribution of different components of the tumor microenvironment (TME). Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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20 pages, 5610 KiB  
Article
Differential B-Cell Receptor Signaling Requirement for Adhesion of Mantle Cell Lymphoma Cells to Stromal Cells
by Laia Sadeghi, Gustav Arvidsson, Magali Merrien, Agata M. Wasik, André Görgens, C.I. Edvard Smith, Birgitta Sander and Anthony P. Wright
Cancers 2020, 12(5), 1143; https://doi.org/10.3390/cancers12051143 - 02 May 2020
Cited by 7 | Viewed by 3611
Abstract
Interactions between lymphoma cells and stromal cells play a key role in promoting tumor survival and development of drug resistance. We identified differences in key signaling pathways between the JeKo-1 and REC-1 mantle cell lymphoma (MCL) cell lines, displaying different patterns of stromal [...] Read more.
Interactions between lymphoma cells and stromal cells play a key role in promoting tumor survival and development of drug resistance. We identified differences in key signaling pathways between the JeKo-1 and REC-1 mantle cell lymphoma (MCL) cell lines, displaying different patterns of stromal cell adhesion and chemotaxis towards stroma-conditioned medium. The identified adhesion-regulated genes reciprocated important aspects of microenvironment-mediated gene modulation in MCL patients. Five-hundred and ninety genes were differently regulated between the cell lines upon adhesion to stromal cells, while 32 genes were similarly regulated in both cell lines. Regulation of B-cell Receptor (BCR) signature genes in adherent cells was specific for JeKo-1. Inhibition of BCR using siRNA or clinically approved inhibitors, Ibrutinib and Acalabrutinib, decreased adhesion of JeKo-1, but not REC-1 cells. Cell surface levels of chemokine receptor CXCR4 were higher in JeKo-1, facilitating migration and adhesion of JeKo-1 but not REC-1 cells. Surface levels of ICAM1 adhesion protein differ for REC-1 and JeKo-1. While ICAM1 played a positive role in adherence of both cell lines to stromal cells, S1PR1 had an inhibitory effect. Our results provide a model framework for further investigation of mechanistic differences in patient-response to new pathway-specific drugs. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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21 pages, 6014 KiB  
Article
Impact of the Monocarboxylate Transporter-1 (MCT1)-Mediated Cellular Import of Lactate on Stemness Properties of Human Pancreatic Adenocarcinoma Cells
by Leontine Sandforth, Nourhane Ammar, Lisa Antonia Dinges, Christoph Röcken, Alexander Arlt, Susanne Sebens and Heiner Schäfer
Cancers 2020, 12(3), 581; https://doi.org/10.3390/cancers12030581 - 03 Mar 2020
Cited by 22 | Viewed by 4320
Abstract
Metabolite exchange between stromal and tumor cells or among tumor cells themselves accompanies metabolic reprogramming in cancer including pancreatic adenocarcinoma (PDAC). Some tumor cells import and utilize lactate for oxidative energy production (reverse Warburg-metabolism) and the presence of these “reverse Warburg“ cells associates [...] Read more.
Metabolite exchange between stromal and tumor cells or among tumor cells themselves accompanies metabolic reprogramming in cancer including pancreatic adenocarcinoma (PDAC). Some tumor cells import and utilize lactate for oxidative energy production (reverse Warburg-metabolism) and the presence of these “reverse Warburg“ cells associates with a more aggressive phenotype and worse prognosis, though the underlying mechanisms are poorly understood. We now show that PDAC cells (BxPc3, A818-6, T3M4) expressing the lactate-importer monocarboxylate transporter-1 (MCT1) are protected by lactate against gemcitabine-induced apoptosis in a MCT1-dependent fashion, contrary to MCT1-negative PDAC cells (Panc1, Capan2). Moreover, lactate administration under glucose starvation, resembling reverse Warburg co a phenotype of BxPc3 and T3M4 cells that confers greater potential of clonal growth upon re-exposure to glucose, along with drug resistance and elevated expression of the stemness marker Nestin and reprogramming factors (Oct4, KLF4, Nanog). These lactate dependent effects on stemness properties are abrogated by the MCT1/lactate-uptake inhibitor 7ACC2 or MCT1 knock-down. Furthermore, the clinical relevance of these observations was supported by detecting co-expression of MCT1 and reprogramming factors in human PDAC tissues. In conclusion, the MCT1-dependent import of lactate supplies “reverse Warburg “PDAC cells with an efficient driver of metabostemness. This condition may essentially contribute to malignant traits including therapy resistance. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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13 pages, 2944 KiB  
Communication
Mesothelial-to-Mesenchymal Transition Contributes to the Generation of Carcinoma-Associated Fibroblasts in Locally Advanced Primary Colorectal Carcinomas
by Carlos H. Gordillo, Pilar Sandoval, Patricia Muñoz-Hernández, Lucía Pascual-Antón, Manuel López-Cabrera and José A. Jiménez-Heffernan
Cancers 2020, 12(2), 499; https://doi.org/10.3390/cancers12020499 - 21 Feb 2020
Cited by 23 | Viewed by 3463
Abstract
During peritoneal metastasis, cancer cells spread from abdominal solid tumors, disseminate through the peritoneal fluid and attach to and invade through mesothelial cells (MCs) that line the peritoneum. Intestinal adenocarcinomas originating in the mucosa infiltrate the submucosa, muscle layer, and serosa in order [...] Read more.
During peritoneal metastasis, cancer cells spread from abdominal solid tumors, disseminate through the peritoneal fluid and attach to and invade through mesothelial cells (MCs) that line the peritoneum. Intestinal adenocarcinomas originating in the mucosa infiltrate the submucosa, muscle layer, and serosa in order to finally colonize the peritoneal cavity. However, the mechanism by which metastatic cells leave the primary tumor and reach the peritoneal cavity has not been previously described. Hence, we investigate whether MCs lining visceral peritoneum, through a mesothelial-to-mesenchymal transition (MMT), are a source of carcinoma-associated fibroblasts (CAFs), which could contribute to cancer progression toward the peritoneal cavity. CAFs detected in biopsies from patients with superficially invasive colorectal cancer differed from locally advanced tumors. An aberrant accumulation of myofibroblasts expressing mesothelial markers was found in the stroma of deeply infiltrative tumors located in the neighborhood of a frequently activated mesothelium. We suggest that MMT is a key event in the early stages of peritoneal dissemination. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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17 pages, 3552 KiB  
Article
Expression of Irisin/FNDC5 in Cancer Cells and Stromal Fibroblasts of Non-Small Cell Lung Cancer
by Katarzyna Nowinska, Karolina Jablonska, Konrad Pawelczyk, Aleksandra Piotrowska, Aleksandra Partynska, Agnieszka Gomulkiewicz, Urszula Ciesielska, Ewa Katnik, Jedrzej Grzegrzolka, Natalia Glatzel-Plucinska, Katarzyna Ratajczak-Wielgomas, Marzenna Podhorska-Okolow and Piotr Dziegiel
Cancers 2019, 11(10), 1538; https://doi.org/10.3390/cancers11101538 - 11 Oct 2019
Cited by 25 | Viewed by 4172
Abstract
Background: Recent in vitro studies have indicated that irisin inhibits proliferation, migration and epithelial-mesenchymal transition. Irisin expression has not been studied in tumour tissues of non-small cell lung cancer (NSCLC) patients yet. The aim of the study was to determine the irisin expression [...] Read more.
Background: Recent in vitro studies have indicated that irisin inhibits proliferation, migration and epithelial-mesenchymal transition. Irisin expression has not been studied in tumour tissues of non-small cell lung cancer (NSCLC) patients yet. The aim of the study was to determine the irisin expression in NSCLCs in comparison to the clinicopathological factors and expression of TTF-1, p63 and Ki-67. Material and methods: Tissue microarrays with 729 NSCLC and 140 non-malignant lung tissue (NMLT) were used to perform immunohistochemical reactions. Laser Capture Microdissection (LCM) was used to collect cancer and stromal cells from NSCLCs. FNDC5 expression was tested for LCM samples, 75 NSCLCs and 25 NMLTs with the RT-PCR technique. Western-blot, immunofluorescence reaction and RT-PCR assays were performed on lung cancer cell lines. Results: Irisin expression was observed in NSCLC cancer cells and stromal fibroblasts. In cancer cells, irisin expression was decreased in higher grades (G) of malignancy, tumour size (T) and according to lymph node metastasis. In stromal cells, irisin expression was increased in higher G and advanced T. A shorter overall survival was observed in patients with higher irisin expression in NSCLC stromal cells. Conclusions: Irisin expression in stromal fibroblasts may influence cancer cell proliferation and may be a prognostic factor for survival in NSCLC. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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17 pages, 3644 KiB  
Article
Impact of Fibroblast-Derived SPARC on Invasiveness of Colorectal Cancer Cells
by Daniel Drev, Felix Harpain, Andrea Beer, Anton Stift, Elisabeth S. Gruber, Martin Klimpfinger, Sabine Thalhammer, Andrea Reti, Lukas Kenner, Michael Bergmann and Brigitte Marian
Cancers 2019, 11(10), 1421; https://doi.org/10.3390/cancers11101421 - 24 Sep 2019
Cited by 20 | Viewed by 3353
Abstract
Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein modulating cell-matrix interactions and was found up-regulated in tumor stroma. To explore the effect of high stromal SPARC on colorectal cancer (CRC) cell behavior and clinical outcome, this study determined SPARC [...] Read more.
Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein modulating cell-matrix interactions and was found up-regulated in tumor stroma. To explore the effect of high stromal SPARC on colorectal cancer (CRC) cell behavior and clinical outcome, this study determined SPARC expression in patients suffering from stage II and III CRC using a publicly available mRNA data set and immunohistochemistry of tissue microarray sections. Moreover, in vitro co-culture models using CRC cell lines together with colon-associated fibroblasts were established to determine the effect of fibroblast-derived SPARC on cancer cells. In 466 patient samples, high SPARC mRNA was associated with a shorter disease-free survival. In 99 patients of the tissue microarray cohort, high stromal SPARC in the primary tumor was an independent predictor of shorter survival in patients with relapse (27 cases; HR = 4574, p = 0.004). In CRC cell lines, SPARC suppressed phosphorylation of focal adhesion kinase and stimulated cell migration. Colon-associated fibroblasts increased migration velocity by 30% and doubled track-length in SPARC-dependent manner. In a 3D co-culture system, fibroblast-derived SPARC enhanced tumor cell invasion. Taken together, stromal SPARC had a pro-metastatic impact in vitro and was a characteristic of aggressive tumors with poor prognosis in CRC patients. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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Review

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14 pages, 828 KiB  
Review
The Interplay of Tumor Stroma and Translational Factors in Endometrial Cancer
by Monika Sobočan, Maria Anna Smolle, Christoph Schatz and Johannes Haybaeck
Cancers 2020, 12(8), 2074; https://doi.org/10.3390/cancers12082074 - 27 Jul 2020
Cited by 10 | Viewed by 2278
Abstract
Endometrial cancer (EC) is a common gynecologic malignancy which continues to have a poor prognosis in advanced stages due to current therapeutic limitations. A significant mechanism of chemoresistance in EC has been shown to also be the enhancement of epithelial to mesenchymal transition [...] Read more.
Endometrial cancer (EC) is a common gynecologic malignancy which continues to have a poor prognosis in advanced stages due to current therapeutic limitations. A significant mechanism of chemoresistance in EC has been shown to also be the enhancement of epithelial to mesenchymal transition (EMT) and the subsequent obtainment of stem cell-like characteristics of EC. Current evidence on EMT in EC however fails to explain the relationship leading to an EMT signaling enhancement. Our review therefore focuses on understanding eukaryotic translation initiation factors (eIFs) as key regulators of the translational process in enhancing EMT and subsequently impacting higher chemoresistance of EC. We identified pathways connected to the development of a microenvironment for EMT, inducers of the process specifically related to estrogen receptors as well as their interplay with eIFs. In the future, investigation elucidating the translational biology of EC in EMT may therefore focus on the signaling between protein kinase RNA-like ER kinase (PERK) and eIF2alpha as well as eIF3B. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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30 pages, 621 KiB  
Review
The CCL5/CCR5 Axis in Cancer Progression
by Donatella Aldinucci, Cinzia Borghese and Naike Casagrande
Cancers 2020, 12(7), 1765; https://doi.org/10.3390/cancers12071765 - 02 Jul 2020
Cited by 185 | Viewed by 17819
Abstract
Tumor cells can “hijack” chemokine networks to support tumor progression. In this context, the C-C chemokine ligand 5/C-C chemokine receptor type 5 (CCL5/CCR5) axis is gaining increasing attention, since abnormal expression and activity of CCL5 and its receptor CCR5 have been found in [...] Read more.
Tumor cells can “hijack” chemokine networks to support tumor progression. In this context, the C-C chemokine ligand 5/C-C chemokine receptor type 5 (CCL5/CCR5) axis is gaining increasing attention, since abnormal expression and activity of CCL5 and its receptor CCR5 have been found in hematological malignancies and solid tumors. Numerous preclinical in vitro and in vivo studies have shown a key role of the CCL5/CCR5 axis in cancer, and thus provided the rationale for clinical trials using the repurposed drug maraviroc, a CCR5 antagonist used to treat HIV/AIDS. This review summarizes current knowledge on the role of the CCL5/CCR5 axis in cancer. First, it describes the involvement of the CCL5/CCR5 axis in cancer progression, including autocrine and paracrine tumor growth, ECM (extracellular matrix) remodeling and migration, cancer stem cell expansion, DNA damage repair, metabolic reprogramming, and angiogenesis. Then, it focuses on individual hematological and solid tumors in which CCL5 and CCR5 have been studied preclinically. Finally, it discusses clinical trials of strategies to counteract the CCL5/CCR5 axis in different cancers using maraviroc or therapeutic monoclonal antibodies. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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35 pages, 2211 KiB  
Review
Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination
by Angelica Avagliano, Giuseppe Fiume, Maria Rosaria Ruocco, Nunzia Martucci, Eleonora Vecchio, Luigi Insabato, Daniela Russo, Antonello Accurso, Stefania Masone, Stefania Montagnani and Alessandro Arcucci
Cancers 2020, 12(6), 1697; https://doi.org/10.3390/cancers12061697 - 26 Jun 2020
Cited by 25 | Viewed by 5529
Abstract
The stromal microenvironment regulates mammary gland development and tumorigenesis. In normal mammary glands, the stromal microenvironment encompasses the ducts and contains fibroblasts, the main regulators of branching morphogenesis. Understanding the way fibroblast signaling pathways regulate mammary gland development may offer insights into the [...] Read more.
The stromal microenvironment regulates mammary gland development and tumorigenesis. In normal mammary glands, the stromal microenvironment encompasses the ducts and contains fibroblasts, the main regulators of branching morphogenesis. Understanding the way fibroblast signaling pathways regulate mammary gland development may offer insights into the mechanisms of breast cancer (BC) biology. In fact, the unregulated mammary fibroblast signaling pathways, associated with alterations in extracellular matrix (ECM) remodeling and branching morphogenesis, drive breast cancer microenvironment (BCM) remodeling and cancer growth. The BCM comprises a very heterogeneous tissue containing non-cancer stromal cells, namely, breast cancer-associated fibroblasts (BCAFs), which represent most of the tumor mass. Moreover, the different components of the BCM highly interact with cancer cells, thereby generating a tightly intertwined network. In particular, BC cells activate recruited normal fibroblasts in BCAFs, which, in turn, promote BCM remodeling and metastasis. Thus, comparing the roles of normal fibroblasts and BCAFs in the physiological and metastatic processes, could provide a deeper understanding of the signaling pathways regulating BC dissemination. Here, we review the latest literature describing the structure of the mammary gland and the BCM and summarize the influence of epithelial-mesenchymal transition (EpMT) and autophagy in BC dissemination. Finally, we discuss the roles of fibroblasts and BCAFs in mammary gland development and BCM remodeling, respectively. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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18 pages, 1731 KiB  
Review
Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment
by Jeffrey Norton, Deshka Foster, Malini Chinta, Ashley Titan and Michael Longaker
Cancers 2020, 12(5), 1347; https://doi.org/10.3390/cancers12051347 - 25 May 2020
Cited by 77 | Viewed by 7866
Abstract
Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis [...] Read more.
Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis called desmoplasia. Desmoplastic stroma is coopted by the tumor as a support structure and CAFs aid in tumor growth, invasion, and metastases. This stroma is caused by cancer associated fibroblasts (CAFs), which lay down extensive connective tissue in and around the tumor cells. CAFs represent a heterogeneous population of cells that produce various paracrine molecules such as transforming growth factor-beta (TGF-beta) and platelet derived growth factors (PDGFs) that aid tumor growth, local invasion, and development of metastases. The hard, fibrotic shell of desmoplasia serves as a barrier to the infiltration of both chemo- and immunotherapy drugs and host immune cells to the tumor. Although there have been recent improvements in chemotherapy and surgical techniques for management of pancreatic cancer, the majority of patients will die from this disease. Therefore, new treatment strategies are clearly needed. CAFs represent an under-explored potential therapeutic target. This paper discusses what we know about the role of CAFs in pancreatic cancer cell growth, invasion, and metastases. Additionally, we present different strategies that are being and could be explored as anti-CAF treatments for pancreatic cancer. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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13 pages, 939 KiB  
Review
Role of Tumor and Stroma-Derived IGF/IGFBPs in Pancreatic Cancer
by Divya Thomas and Prakash Radhakrishnan
Cancers 2020, 12(5), 1228; https://doi.org/10.3390/cancers12051228 - 13 May 2020
Cited by 13 | Viewed by 3925
Abstract
Pancreatic cancer (PC) is the utmost stroma-rich cancer, which is accompanied by fibrotic reactions that stimulate interactions between tumor cells and stroma to promote tumor progression. Considerable research evidence denotes that insulin-like growth factor (IGF)/IGF binding proteins (IGFBP) signaling axis facilitate tumor growth, [...] Read more.
Pancreatic cancer (PC) is the utmost stroma-rich cancer, which is accompanied by fibrotic reactions that stimulate interactions between tumor cells and stroma to promote tumor progression. Considerable research evidence denotes that insulin-like growth factor (IGF)/IGF binding proteins (IGFBP) signaling axis facilitate tumor growth, metastasis, drug resistance, and thereby facilitate PC into an advanced stage. The six members of IGFBPs were initially considered as passive carriers of free IGFs; however, current evidence revealed their functions beyond the endocrine role in IGF transport. Though numerous efforts have been made in blocking IGF/IGFBPs, the targeted therapies remain unsuccessful due to the complexity of tumor-stromal interactions in the pancreas. In this review, we explore the emerging evidence of the various roles of the tumor as well as stroma derived IGF/IGFBPs and highlight as a novel therapeutic target against PC progression. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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Other

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2 pages, 170 KiB  
Addendum
Addendum: Witschen, P.M., et al. Tumor Cell Associated Hyaluronan-CD44 Signaling Promotes Pro-Tumor Inflammation in Breast Cancer. Cancers 2020, 12, 1325
by Patrice M. Witschen, Thomas S. Chaffee, Nicholas J. Brady, Danielle N. Huggins, Todd P. Knutson, Rebecca S. LaRue, Sarah A. Munro, Lyubov Tiegs, James B. McCarthy, Andrew C. Nelson and Kathryn L. Schwertfeger
Cancers 2020, 12(10), 2736; https://doi.org/10.3390/cancers12102736 - 23 Sep 2020
Cited by 4 | Viewed by 1557
Abstract
The authors wish to make the following corrections to this paper [...] Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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