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28 pages, 5287 KiB

Open AccessArticle

Persistent Inflammatory Stimulation Drives the Conversion of MSCs to Inflammatory CAFs That Promote Pro-Metastatic Characteristics in Breast Cancer Cells

by Linor Rubinstein-Achiasaf, Dina Morein, Hagar Ben-Yaakov, Yulia Liubomirski, Tsipi Meshel, Eti Elbaz, Orly Dorot, Edward Pichinuk, Michael Gershovits, Miguel Weil and Adit Ben-Baruch

Cancers 2021, 13(6), 1472; https://doi.org/10.3390/cancers13061472 - 23 Mar 2021

Cited by 26 | Viewed by 4862

Abstract

The pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) are expressed simultaneously and have tumor-promoting roles in breast cancer. In parallel, mesenchymal stem cells (MSCs) undergo conversion at the tumor site to cancer-associated fibroblasts (CAFs), which are generally connected to [...] Read more.

The pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) are expressed simultaneously and have tumor-promoting roles in breast cancer. In parallel, mesenchymal stem cells (MSCs) undergo conversion at the tumor site to cancer-associated fibroblasts (CAFs), which are generally connected to enhanced tumor progression. Here, we determined the impact of consistent inflammatory stimulation on stromal cell plasticity. MSCs that were persistently stimulated by TNFα + IL-1β (generally 14–18 days) gained a CAF-like morphology, accompanied by prominent changes in gene expression, including in stroma/fibroblast-related genes. These CAF-like cells expressed elevated levels of vimentin and fibroblast activation protein (FAP) and demonstrated significantly increased abilities to contract collagen gels. Moreover, they gained the phenotype of inflammatory CAFs, as indicated by the reduced expression of α smooth muscle actin (αSMA), increased proliferation, and elevated expression of inflammatory genes and proteins, primarily inflammatory chemokines. These inflammatory CAFs released factors that enhanced tumor cell dispersion, scattering, and migration; the inflammatory CAF-derived factors elevated cancer cell migration by stimulating the chemokine receptors CCR2, CCR5, and CXCR1/2 and Ras-activating receptors, expressed by the cancer cells. Together, these novel findings demonstrate that chronic inflammation can induce MSC-to-CAF conversion, leading to the generation of tumor-promoting inflammatory CAFs. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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23 pages, 5261 KiB

Open AccessArticle

Mast Cell-Derived SAMD14 Is a Novel Regulator of the Human Prostate Tumor Microenvironment

by Linda K. H. Teng, Brooke A. Pereira, Shivakumar Keerthikumar, Cheng Huang, Birunthi Niranjan, Sophie N. Lee, Michelle Richards, Ralf B. Schittenhelm, Luc Furic, David L. Goode, Mitchell G. Lawrence, Renea A. Taylor, Stuart J. Ellem, Gail P. Risbridger and Natalie L. Lister

Cancers 2021, 13(6), 1237; https://doi.org/10.3390/cancers13061237 - 11 Mar 2021

Cited by 11 | Viewed by 2948

Abstract

Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs), which combine [...] Read more.

Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs), which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remain poorly understood. To identify molecular changes that may alter resident MC function in the prostate tumor microenvironment, we profiled the transcriptome of human prostate MCs isolated from patient-matched non-tumor and tumor-associated regions of fresh radical prostatectomy tissue. Transcriptomic profiling revealed a distinct gene expression profile of MCs isolated from prostate tumor regions, including the downregulation of SAMD14, a putative tumor suppressor gene. Proteomic profiling revealed that overexpression of SAMD14 in HMC-1 altered the secretion of proteins associated with immune regulation and extracellular matrix processes. To assess MC biological function within a model of the prostate tumor microenvironment, HMC-1-SAMD14+ conditioned media was added to co-cultures of primary prostatic CAFs and prostate epithelium. HMC-1-SAMD14+ secretions were shown to reduce the deposition and alignment of matrix produced by CAFs and suppress pro-tumorigenic prostate epithelial morphology. Overall, our data present the first profile of human MCs derived from prostate cancer patient specimens and identifies MC-derived SAMD14 as an important mediator of MC phenotype and function within the prostate tumor microenvironment. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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17 pages, 3254 KiB

Open AccessArticle

Role of Omentin in Obesity Paradox in Lung Cancer

by Sheetal Parida, Sumit Siddharth and Dipali Sharma

Cancers 2021, 13(2), 275; https://doi.org/10.3390/cancers13020275 - 13 Jan 2021

Cited by 11 | Viewed by 2896

Abstract

Lung cancer remains the second-most-common cancer worldwide and is associated with the highest number of cancer-related mortality. While tobacco smoking is the most important risk factor for lung cancer, many other lifestyles and occupational factors significantly contribute. Obesity is a growing global health [...] Read more.

Lung cancer remains the second-most-common cancer worldwide and is associated with the highest number of cancer-related mortality. While tobacco smoking is the most important risk factor for lung cancer, many other lifestyles and occupational factors significantly contribute. Obesity is a growing global health concern and contributes to ~30% cancer-related mortality, but unlike other lifestyle diseases, lung cancer is negatively associated with obesity. We meta-analyzed multiple case-control studies confirming increased survival and better outcomes in overweight and obese lung cancer patients. Tumor heterogeneity analysis showed significant enrichment of adipocytes and preadipocytes in normal lungs compared to lung cancers. Interestingly, one of the understudied adipokine, omentin, was significantly and consistently lower in lung neoplasms compared to normal lungs. Omentin has been examined in relation to osteoarthritis, inflammatory bowel disease, cardiovascular diseases, diabetes, chronic liver disease, psoriasis and some other cancers. Aberrant expression of omentin has been reported in solid tumors; however, little is known about its role in lung cancer. We found omentin to be consistently downregulated in lung cancers, and it exhibited a negative correlation with important transcription factors FOXA1, EN1, FOXC1 and ELK4. We, therefore, suggest that omentin may serve as a prognostic factor in lung cancer and explain the “obesity paradox” in lung cancer. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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24 pages, 2002 KiB

Open AccessArticle

The Extracellular Bone Marrow Microenvironment—A Proteomic Comparison of Constitutive Protein Release by In Vitro Cultured Osteoblasts and Mesenchymal Stem Cells

by Elise Aasebø, Even Birkeland, Frode Selheim, Frode Berven, Annette K. Brenner and Øystein Bruserud

Cancers 2021, 13(1), 62; https://doi.org/10.3390/cancers13010062 - 28 Dec 2020

Cited by 16 | Viewed by 2849

Abstract

Mesenchymal stem cells (MSCs) and osteoblasts are bone marrow stromal cells that contribute to the formation of stem cell niches and support normal hematopoiesis, leukemogenesis and development of metastases from distant cancers. This support is mediated through cell–cell contact, release of soluble mediators [...] Read more.

Mesenchymal stem cells (MSCs) and osteoblasts are bone marrow stromal cells that contribute to the formation of stem cell niches and support normal hematopoiesis, leukemogenesis and development of metastases from distant cancers. This support is mediated through cell–cell contact, release of soluble mediators and formation of extracellular matrix. By using a proteomic approach, we characterized the protein release by in vitro cultured human MSCs (10 donors) and osteoblasts (nine donors). We identified 1379 molecules released by these cells, including 340 proteins belonging to the GO-term Extracellular matrix. Both cell types released a wide range of functionally heterogeneous proteins including extracellular matrix molecules (especially collagens), several enzymes and especially proteases, cytokines and soluble adhesion molecules, but also several intracellular molecules including chaperones, cytoplasmic mediators, histones and non-histone nuclear molecules. The levels of most proteins did not differ between MSCs and osteoblasts, but 82 proteins were more abundant for MSC (especially extracellular matrix proteins and proteases) and 36 proteins more abundant for osteoblasts. Finally, a large number of exosomal proteins were identified. To conclude, MSCs and osteoblasts show extracellular release of a wide range of functionally diverse proteins, including several extracellular matrix molecules known to support cancer progression (e.g., metastases from distant tumors, increased relapse risk for hematological malignancies), and the large number of identified exosomal proteins suggests that exocytosis is an important mechanism of protein release. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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26 pages, 9142 KiB

Open AccessArticle

Calcitriol in the Presence of Conditioned Media from Metastatic Breast Cancer Cells Enhances Ex Vivo Polarization of M2 Alternative Murine Bone Marrow-Derived Macrophages

by Artur Anisiewicz, Natalia Łabędź, Izabela Krauze and Joanna Wietrzyk

Cancers 2020, 12(11), 3485; https://doi.org/10.3390/cancers12113485 - 23 Nov 2020

Cited by 9 | Viewed by 4454

Abstract

In this study, we differentiated murine bone marrow-derived macrophages (BMDMs) into M0, M1, and M2 in the presence or absence of calcitriol. Real-time PCR analysis of gene expression, FACS analysis of surface markers, and chemokine/cytokine production assays were performed. In addition, the effect [...] Read more.

In this study, we differentiated murine bone marrow-derived macrophages (BMDMs) into M0, M1, and M2 in the presence or absence of calcitriol. Real-time PCR analysis of gene expression, FACS analysis of surface markers, and chemokine/cytokine production assays were performed. In addition, the effect of the conditioned media (CM) from murine breast cancer 4T1 (metastatic) and 67NR (non-metastatic) and Eph4-Ev (normal) cells with and without calcitriol on the polarization of M1/M2 cells was determined. We found that calcitriol enhanced the differentiation of M2 macrophages, which was manifested by increased expression of Cd206 and Spp1 mRNA and CD36, Arg, and CCL2 in M2 BMDMs and by decreased expression of Cd80 and Spp1 mRNA and IL-1, IL-6, OPN, and iNOS in M1 BMDMs. 4T1 CM showed a higher effect on the gene and protein expression in macrophages than 67NR and Eph4-Ev, with the greatest effect observed on M2 macrophages which increased their differentiation and properties characteristic of alternative macrophages. Moreover, M2 macrophages differentiated with calcitriol-stimulated migration of 4T1 and 67NR cells through fibronectin and collagen type IV, respectively. Overall, our results indicated that vitamin D supplementation may not always be beneficial, especially in relation to cancers causing excessive, pathological activation of the immune system. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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22 pages, 5683 KiB

Open AccessArticle

Carcinoma-Associated Fibroblasts Promote Growth of Sox2-Expressing Breast Cancer Cells

by Angela Dittmer and Jürgen Dittmer

Cancers 2020, 12(11), 3435; https://doi.org/10.3390/cancers12113435 - 19 Nov 2020

Cited by 14 | Viewed by 3005

Abstract

CAFs (Carcinoma-associated fibroblasts) play an important role in cancer progression. For instance, they promote resistance to anti-estrogens, such as fulvestrant. Here, we show that, in ERα-positive breast cancer cell lines, the cocktail of factors secreted by CAFs (CAF-CM) induce the expression of the [...] Read more.

CAFs (Carcinoma-associated fibroblasts) play an important role in cancer progression. For instance, they promote resistance to anti-estrogens, such as fulvestrant. Here, we show that, in ERα-positive breast cancer cell lines, the cocktail of factors secreted by CAFs (CAF-CM) induce the expression of the embryonal stem cell transcription factor Sox2 (sex determining region Y (SRY)-box 2). Long-term exposure to CAF-CM was able to give rise to very high Sox2 levels both in the absence and presence of fulvestrant. IL-6 (interleukin-6), a major component of CAF-CM, failed to raise Sox2 expression. In MCF-7 sublines established in the presence of CAF-CM, almost all cells showed Sox2 expression, whereas long-term treatment of T47D cells with CAF-CM resulted in a ~60-fold increase in the proportions of two distinct populations of Sox2 high and low expresser cells. Exposure of BT474 cells to CAF-CM raised the fraction of Sox2 high expresser cells by ~3-fold. Cell sorting based on CD44 and CD24 expression or ALDH (aldehyde dehydrogenase) activity revealed that most Sox2 high expresser cells were not CD44^hi/CD24^lo- or ALDH-positive cells suggesting that they were not CSCs (cancer stem cells), though CD44 played a role in Sox2 expression. Functionally, Sox2 was found to protect CAF-CM-treated cells against apoptosis and to allow higher growth activity in the presence of fulvestrant. Mechanistically, the key drivers of Sox2 expression was found to be STAT3 (Signal transducer and activator of transcription 3), Bcl-3 (B-cell lymphoma 3) and the PI3K (Phosphoinositide 3-kinase)/AKT pathway, whose activities/expression can all be upregulated by CAF-CM. These data suggest that CAF-CM induces Sox2 expression in non-CSCs by activating proteins involved in growth control and drug resistance, leading to higher protection against apoptosis. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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17 pages, 2754 KiB

Open AccessArticle

B Cells and Tertiary Lymphoid Structures Influence Survival in Lung Cancer Patients with Resectable Tumors

by Jun Tang, Daniel Ramis-Cabrer, Víctor Curull, Xuejie Wang, Mercé Mateu-Jiménez, Lara Pijuan, Xavier Duran, Liyun Qin, Alberto Rodríguez-Fuster, Rafael Aguiló and Esther Barreiro

Cancers 2020, 12(9), 2644; https://doi.org/10.3390/cancers12092644 - 16 Sep 2020

Cited by 39 | Viewed by 3416

Abstract

Immune profile of B and T cells and tertiary lymphoid structures (TLSs) may differ in tumors of lung cancer (LC) patients with/without chronic obstructive pulmonary disease (COPD), and may also influence patient survival. We sought to analyze: (1) TLSs, germinal centers (GCs), B [...] Read more.

Immune profile of B and T cells and tertiary lymphoid structures (TLSs) may differ in tumors of lung cancer (LC) patients with/without chronic obstructive pulmonary disease (COPD), and may also influence patient survival. We sought to analyze: (1) TLSs, germinal centers (GCs), B and T cells, and (2) associations of the immune biomarkers with the patients’ 10-year overall survival (OS). TLSs (numbers and area), B [cluster of differentiation (CD) 20], and T (CD3), and GCs cells were identified in both tumor and non-tumor specimens (thoracotomy) from 90 LC-COPD patients and 43 LC-only patients. Ten-year OS was analyzed in the patients. Immune profile in tumors of LC-COPD versus LC: TLS numbers and areas significantly decreased in tumors of LC-COPD compared to LC patients. No significant differences were observed in tumors between LC-COPD and LC patients for B or T cells. Immune profile in tumors versus non-tumor specimens: TLS areas and B cells significantly increased, T cells significantly decreased in tumors of both LC and LC-COPD patients. Survival: in LC-COPD patients: greater area of TLSs and proportion of B cells were associated with longer survival rates. The immune tumor microenvironment differs in patients with underlying COPD and these different phenotypes may eventually impact the response to immunotherapy in patients with LC. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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18 pages, 3460 KiB

Open AccessArticle

Extracellular Neuroglobin as a Stress-Induced Factor Activating Pre-Adaptation Mechanisms against Oxidative Stress and Chemotherapy-Induced Cell Death in Breast Cancer

by Marco Fiocchetti, Virginia Solar Fernandez, Marco Segatto, Stefano Leone, Paolo Cercola, Annalisa Massari, Francesco Cavaliere and Maria Marino

Cancers 2020, 12(9), 2451; https://doi.org/10.3390/cancers12092451 - 29 Aug 2020

Cited by 10 | Viewed by 2838

Abstract

Components of tumor microenvironment, including tumor and/or stromal cells-derived factors, exert a critical role in breast cancer (BC) progression. Here we evaluated the possible role of neuroglobin (NGB), a monomeric globin that acts as a compensatory protein against oxidative and apoptotic processes, as [...] Read more.

Components of tumor microenvironment, including tumor and/or stromal cells-derived factors, exert a critical role in breast cancer (BC) progression. Here we evaluated the possible role of neuroglobin (NGB), a monomeric globin that acts as a compensatory protein against oxidative and apoptotic processes, as part of BC microenvironment. The extracellular NGB levels were evaluated by immunofluorescence of BC tissue sections and by Western blot of the culture media of BC cell lines. Moreover, reactive oxygen species (ROS) generation, cell apoptosis, and cell migration were evaluated in different BC cells and non-tumorigenic epithelial mammary cells treated with BC cells (i.e., Michigan Cancer Foundation-7, MCF-7) conditioned culture media and extracellular NGB. Results demonstrate that NGB is a component of BC microenvironment. NGB is released in tumor microenvironment by BC cells only under oxidative stress conditions where it can act as autocrine/paracrine factor able to communicate cell resilience against oxidative stress and chemotherapeutic treatment. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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16 pages, 2534 KiB

Open AccessArticle

Neutrophil Extracellular Traps (NETs) Promote Pro-Metastatic Phenotype in Human Breast Cancer Cells through Epithelial–Mesenchymal Transition

by Karina Martins-Cardoso, Vitor H. Almeida, Kayo M. Bagri, Maria Isabel Doria Rossi, Claudia S. Mermelstein, Sandra König and Robson Q. Monteiro

Cancers 2020, 12(6), 1542; https://doi.org/10.3390/cancers12061542 - 11 Jun 2020

Cited by 86 | Viewed by 5471

Abstract

Neutrophil extracellular traps (NETs) have been associated with several steps of tumor progression, including primary growth and metastasis. One of the key features for the acquisition of the metastatic ability is the epithelial–mesenchymal transition (EMT), a complex cellular program. In this study, we [...] Read more.

Neutrophil extracellular traps (NETs) have been associated with several steps of tumor progression, including primary growth and metastasis. One of the key features for the acquisition of the metastatic ability is the epithelial–mesenchymal transition (EMT), a complex cellular program. In this study, we evaluated the ability of isolated NETs in modulating the pro-metastatic phenotype of human breast cancer cells. Tumor cells were treated with isolated NETs and then samples were generated for cell migration, quantitative RT-PCR, western blotting, immunofluorescence, and flow cytometry assays. RNA-seq data from The Cancer Genome Atlas (TCGA) database were assessed. NETs changed the typical epithelial morphology of MCF7 cells into a mesenchymal phenotype, a process that was accompanied by enhanced migratory properties. Additional EMT traits were observed: increased expression of N-cadherin and fibronectin, while the E-cadherin expression was repressed. Notably, NETs positively regulated the gene expression of several factors linked to the pro-inflammatory and pro-metastatic properties. Analyses of TCGA data showed that samples from breast cancer patients exhibit a significant correlation between pro-tumoral and neutrophil signature gene expression, including several EMT and pro-metastatic factors. Therefore, NETs drive pro-metastatic phenotype in human breast cancer cells through the activation of the EMT program. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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15 pages, 3481 KiB

Open AccessArticle

Stiffer Matrix Accelerates Migration of Hepatocellular Carcinoma Cells through Enhanced Aerobic Glycolysis Via the MAPK-YAP Signaling

by Qiu-Ping Liu, Qing Luo, Bin Deng, Yang Ju and Guan-Bin Song

Cancers 2020, 12(2), 490; https://doi.org/10.3390/cancers12020490 - 19 Feb 2020

Cited by 63 | Viewed by 5324

Abstract

Increased extracellular matrix (ECM) stiffness and metabolic reprogramming of cancer cells are two fundamental mediators of tumor progression, including hepatocellular carcinoma (HCC). Yet, the correlation between ECM stiffness and excessive aerobic glycolysis in promoting the development of HCC remains unknown. Here, we demonstrated [...] Read more.

Increased extracellular matrix (ECM) stiffness and metabolic reprogramming of cancer cells are two fundamental mediators of tumor progression, including hepatocellular carcinoma (HCC). Yet, the correlation between ECM stiffness and excessive aerobic glycolysis in promoting the development of HCC remains unknown. Here, we demonstrated that stiffer ECM promotes HCC cell migration depending on their accelerated aerobic glycolysis. Our results also indicated that stiffer ECM-induced YAP activation plays a major role in promoting aerobic glycolysis of HCC cells. Moreover, we showed that JNK and p38 MAPK signaling are critical for mediating YAP activation in HCC cells. Together, our findings established that the MAPK-YAP signaling cascade that act as a mechanotransduction pathway is essential for promoting HCC cell aerobic glycolysis and migration in response to ECM stiffness. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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20 pages, 4787 KiB

Open AccessArticle

Patient-Derived Scaffolds of Colorectal Cancer Metastases as an Organotypic 3D Model of the Liver Metastatic Microenvironment

by Edoardo D’Angelo, Dipa Natarajan, Francesca Sensi, Omolola Ajayi, Matteo Fassan, Enzo Mammano, Pierluigi Pilati, Piero Pavan, Silvia Bresolin, Melissa Preziosi, Rosa Miquel, Yoh Zen, Shilpa Chokshi, Krishna Menon, Nigel Heaton, Gaya Spolverato, Martina Piccoli, Roger Williams, Luca Urbani and Marco Agostini

Cancers 2020, 12(2), 364; https://doi.org/10.3390/cancers12020364 - 5 Feb 2020

Cited by 46 | Viewed by 4893

Abstract

The liver is the most common site for colorectal cancer (CRC) metastasis and there is an urgent need for new tissue culture models to study colorectal cancer liver metastasis (CRLM) as current models do not mimic the biological, biochemical, and structural characteristics of [...] Read more.

The liver is the most common site for colorectal cancer (CRC) metastasis and there is an urgent need for new tissue culture models to study colorectal cancer liver metastasis (CRLM) as current models do not mimic the biological, biochemical, and structural characteristics of the metastatic microenvironment. Decellularization provides a novel approach for the study of the cancer extracellular matrix (ECM) as decellularized scaffolds retain tissue-specific features and biological properties. In the present study, we created a 3D model of CRC and matched CRLM using patient-derived decellularized ECM scaffolds seeded with the HT-29 CRC cell line. Here, we show an increased HT-29 cell proliferation and migration capability when cultured in cancer-derived scaffolds compared to same-patient healthy colon and liver tissues. HT-29 cells cultured in CRLM scaffolds also displayed an indication of epithelial-mesenchymal transition (EMT), with a loss of E-cadherin and increased Vimentin expression. EMT was confirmed by gene expression profiling, with the most represented biological processes in CRLM-seeded scaffolds involving demethylation, deacetylation, a cellular response to stress metabolic processes, and a response to the oxygen level and starvation. HT-29 cells cultured in cancer-specific 3D microenvironments showed a reduced response to treatment with 5-fluorouracil and 5-fluorouracil combined with Irinotecan when used at a standard IC₅₀ (as determined in the 2D culture). Our 3D culture system with patient-derived tissue-specific decellularized ECM better recapitulates the metastatic microenvironment compared to conventional 2D culture conditions and represents a relevant approach for the study of CRLM progression and assessing the response to chemotherapy agents. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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16 pages, 7443 KiB

Open AccessArticle

JNK Pathway Mediates Low Oxygen Level Induced Epithelial–Mesenchymal Transition and Stemness Maintenance in Colorectal Cancer Cells

by Shing Yau Tam, Vincent W.C. Wu and Helen K.W. Law

Cancers 2020, 12(1), 224; https://doi.org/10.3390/cancers12010224 - 16 Jan 2020

Cited by 29 | Viewed by 3577

Abstract

(1) Background: Epithelial–mesenchymal transition (EMT) and cancer cell stemness maintenance (SM) are important factors for cancer metastasis. Although hypoxia has been considered as a possible factor for EMT induction and promotion of SM, studies in this area, apart from hypoxia-inducible factor (HIF) pathways [...] Read more.

(1) Background: Epithelial–mesenchymal transition (EMT) and cancer cell stemness maintenance (SM) are important factors for cancer metastasis. Although hypoxia has been considered as a possible factor for EMT induction and promotion of SM, studies in this area, apart from hypoxia-inducible factor (HIF) pathways and severe hypoxia, are scant. This study aimed to evaluate the effects of different oxygen levels on EMT induction and SM and elucidate the signaling pathways involved in colorectal cancer cells. (2) Methods: Cell morphological analysis, migration assay, immunofluorescence staining of cytoskeleton and Western blotting were performed on human colorectal cancer cells HT-29, DLD-1, and SW-480 cultured at 1%, 10%, and normal (21%) O₂ levels. The role played by c-Jun N-terminal kinase (JNK) was evaluated through the use of the specific JNK inhibitor SP600125. (3) Results: This study evaluated 1% and 10% O₂ are possible conditions for EMT induction and SM. This study also demonstrated the partial relieve of EMT induction and SM by SP600125, showing the importance of the JNK pathway in these processes. Furthermore, this study proposed a novel pathway on the regulation of Akt by JNK-c-Jun. (4) Conclusions: This study suggests 10% O₂ as another possible condition for EMT induction, and SM and JNK pathways play important roles in these processes through multiple factors. Inhibition of JNK could be explored as treatment for inhibiting metastasis in colorectal cancer cells. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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19 pages, 4377 KiB

Open AccessArticle

Triple-Negative Primary Breast Tumors Induce Supportive Premetastatic Changes in the Extracellular Matrix and Soluble Components of the Lung Microenvironment

by Braeden Medeiros, David Goodale, Carl Postenka, Lori E. Lowes, Patti Kiser, Stephen Hearn, Nikki Salmond, Karla C. Williams and Alison L. Allan

Cancers 2020, 12(1), 172; https://doi.org/10.3390/cancers12010172 - 10 Jan 2020

Cited by 20 | Viewed by 6863

Abstract

The lung is one of the deadliest sites of breast cancer metastasis, particularly in patients with triple-negative (TN) disease. We hypothesized that the presence of a TN primary breast tumor induces changes in the extracellular matrix (ECM) and soluble components of the lung [...] Read more.

The lung is one of the deadliest sites of breast cancer metastasis, particularly in patients with triple-negative (TN) disease. We hypothesized that the presence of a TN primary breast tumor induces changes in the extracellular matrix (ECM) and soluble components of the lung microenvironment that support metastatic behavior. SUM159 (TN) and MCF7 (luminal A) breast cancer cells were injected into mice, and primary breast tumors were established prior to assessing metastatic niche changes. We observed increased CD117⁺ hematopoietic progenitor cells in the bone marrow of SUM159 mice versus MCF7 or control mice (p < 0.05). Relative to mice bearing MCF7 tumors and non-tumor controls, mice bearing SUM159 tumors demonstrated enhanced expression of ECM proteins in the lung (fibronectin, tenascin-c and periostin), with similar changes observed in lung fibroblasts treated with extracellular vesicles (EVs) from TN breast cancer cells (p < 0.05). Exposure to lung-conditioned media (LCM) from SUM159 tumor-bearing mice resulted in increased migration/proliferation of both SUM159 and MCF7 cells relative to the control (p < 0.05). In contrast, LCM from MCF-7 tumor-bearing mice had no such effect. LCM from SUM159 tumor-bearing mice contained 16 unique proteins relative to other LCM conditions, including the metastasis-associated proteins CCL7, FGFR4, GM-CSF, MMP3, thrombospondin-1 and VEGF. These findings suggest for the first time that the TN breast cancer molecular subtype may be an important determinant of premetastatic changes to both the ECM and soluble components of the lung, potentially mediated via breast cancer-derived EVs. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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17 pages, 16249 KiB

Open AccessArticle

Hematopoietic Cells Derived from Cancer Stem Cells Generated from Mouse Induced Pluripotent Stem Cells

by Ghmkin Hassan, Said M. Afify, Neha Nair, Kazuki Kumon, Amira Osman, Juan Du, Hager Mansour, Hagar A Abu Quora, Hend M Nawara, Ayano Satoh, Maram H. Zahra, Nobuhiro Okada, Akimasa Seno and Masaharu Seno

Cancers 2020, 12(1), 82; https://doi.org/10.3390/cancers12010082 - 29 Dec 2019

Cited by 20 | Viewed by 5478

Abstract

Cancer stem cells (CSCs) represent the subpopulation of cancer cells with the ability to differentiate into other cell phenotypes and initiated tumorigenesis. Previously, we reported generating CSCs from mouse induced pluripotent stem cells (miPSCs). Here, we investigated the ability of the CSCs to [...] Read more.

Cancer stem cells (CSCs) represent the subpopulation of cancer cells with the ability to differentiate into other cell phenotypes and initiated tumorigenesis. Previously, we reported generating CSCs from mouse induced pluripotent stem cells (miPSCs). Here, we investigated the ability of the CSCs to differentiate into hematopoietic cells. First, the primary cells were isolated from malignant tumors that were formed by the CSCs. Non-adherent cells (NACs) that arose from adherent cells were collected and their viability, as well as the morphology and expression of hematopoietic cell markers, were analyzed. Moreover, NACs were injected into the tail vein of busulfan conditioned Balb/c nude mice. Finally, CSCs were induced to differentiate to macrophages while using IL3 and SCF. The round nucleated NACs were found to be viable, positive for hematopoietic lineage markers and CD34, and expressed hematopoietic markers, just like homing to the bone marrow. When NACs were injected into mice, Wright–Giemsa staining showed that the number of white blood cells got higher than those in the control mice after four weeks. CSCs also showed the ability to differentiate toward macrophages. CSCs were demonstrated to have the potential to provide progenies with hematopoietic markers, morphology, and homing ability to the bone marrow, which could give new insight into the tumor microenvironment according to the plasticity of CSCs. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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Review

Jump to: Research

17 pages, 1531 KiB

Open AccessReview

Role of MSC in the Tumor Microenvironment

by Ralf Hass

Cancers 2020, 12(8), 2107; https://doi.org/10.3390/cancers12082107 - 29 Jul 2020

Cited by 75 | Viewed by 5191

Abstract

The tumor microenvironment represents a dynamically composed matrix in which tissue-associated cancer cells are embedded together with a variety of further cell types to form a more or less separate organ-like structure. Constantly mutual interactions between cells of the tumor microenvironment promote continuous [...] Read more.

The tumor microenvironment represents a dynamically composed matrix in which tissue-associated cancer cells are embedded together with a variety of further cell types to form a more or less separate organ-like structure. Constantly mutual interactions between cells of the tumor microenvironment promote continuous restructuring and growth in the tumor. A distinct organization of the tumor stroma also facilitates the formation of transient cancer stem cell niches, thereby contributing to progressive and dynamic tumor development. An important but heterogeneous mixture of cells that communicates among the cancer cells and the different tumor-associated cell types is represented by mesenchymal stroma-/stem-like cells (MSC). Following recruitment to tumor sites, MSC can change their functionalities, adapt to the tumor’s metabolism, undergo differentiation and synergize with cancer cells. Vice versa, cancer cells can alter therapeutic sensitivities and change metastatic behavior depending on the type and intensity of this MSC crosstalk. Thus, close cellular interactions between MSC and cancer cells can eventually promote cell fusion by forming new cancer hybrid cells. Consequently, newly acquired cancer cell functions or new hybrid cancer populations enlarge the plasticity of the tumor and counteract successful interventional strategies. The present review article highlights some important features of MSC within the tumor stroma. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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24 pages, 2205 KiB

Open AccessReview

Cellular Plasticity and Tumor Microenvironment in Gliomas: The Struggle to Hit a Moving Target

by Ricardo Gargini, Berta Segura-Collar and Pilar Sánchez-Gómez

Cancers 2020, 12(6), 1622; https://doi.org/10.3390/cancers12061622 - 18 Jun 2020

Cited by 31 | Viewed by 4561

Abstract

Brain tumors encompass a diverse group of neoplasias arising from different cell lineages. Tumors of glial origin have been the subject of intense research because of their rapid and fatal progression. From a clinical point of view, complete surgical resection of gliomas is [...] Read more.

Brain tumors encompass a diverse group of neoplasias arising from different cell lineages. Tumors of glial origin have been the subject of intense research because of their rapid and fatal progression. From a clinical point of view, complete surgical resection of gliomas is highly difficult. Moreover, the remaining tumor cells are resistant to traditional therapies such as radio- or chemotherapy and tumors always recur. Here we have revised the new genetic and epigenetic classification of gliomas and the description of the different transcriptional subtypes. In order to understand the progression of the different gliomas we have focused on the interaction of the plastic tumor cells with their vasculature-rich microenvironment and with their distinct immune system. We believe that a comprehensive characterization of the glioma microenvironment will shed some light into why these tumors behave differently from other cancers. Furthermore, a novel classification of gliomas that could integrate the genetic background and the cellular ecosystems could have profound implications in the efficiency of current therapies as well as in the development of new treatments. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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23 pages, 787 KiB

Open AccessReview

Malignant Pleural Mesothelioma: Genetic and Microenviromental Heterogeneity as an Unexpected Reading Frame and Therapeutic Challenge

by David Michael Abbott, Chandra Bortolotto, Silvia Benvenuti, Andrea Lancia, Andrea Riccardo Filippi and Giulia Maria Stella

Cancers 2020, 12(5), 1186; https://doi.org/10.3390/cancers12051186 - 7 May 2020

Cited by 22 | Viewed by 4770

Abstract

Mesothelioma is a malignancy of serosal membranes including the peritoneum, pleura, pericardium and the tunica vaginalis of the testes. Malignant mesothelioma (MM) is a rare disease with a global incidence in countries like Italy of about 1.15 per 100,000 inhabitants. Malignant Pleural Mesothelioma [...] Read more.

Mesothelioma is a malignancy of serosal membranes including the peritoneum, pleura, pericardium and the tunica vaginalis of the testes. Malignant mesothelioma (MM) is a rare disease with a global incidence in countries like Italy of about 1.15 per 100,000 inhabitants. Malignant Pleural Mesothelioma (MPM) is the most common form of mesothelioma, accounting for approximately 80% of disease. Although rare in the global population, mesothelioma is linked to industrial pollutants and mineral fiber exposure, with approximately 80% of cases linked to asbestos. Due to the persistent asbestos exposure in many countries, a worldwide progressive increase in MPM incidence is expected for the current and coming years. The tumor grows in a loco-regional pattern, spreading from the parietal to the visceral pleura and invading the surrounding structures that induce the clinical picture of pleural effusion, pain and dyspnea. Distant spreading and metastasis are rarely observed, and most patients die from the burden of the primary tumor. Currently, there are no effective treatments for MPM, and the prognosis is invariably poor. Some studies average the prognosis to be roughly one-year after diagnosis. The uniquely poor mutational landscape which characterizes MPM appears to derive from a selective pressure operated by the environment; thus, inflammation and immune response emerge as key players in driving MPM progression and represent promising therapeutic targets. Here we recapitulate current knowledge on MPM with focus on the emerging network between genetic asset and inflammatory microenvironment which characterize the disease as amenable target for novel therapeutic approaches. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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21 pages, 1451 KiB

Open AccessReview

Foes or Friends? Bacteria Enriched in the Tumor Microenvironment of Colorectal Cancer

by Siyang Xu, Wen Yin, Yuling Zhang, Qimei Lv, Yijun Yang and Jin He

Cancers 2020, 12(2), 372; https://doi.org/10.3390/cancers12020372 - 6 Feb 2020

Cited by 28 | Viewed by 5415

Abstract

Colorectal cancer (CRC) is the second most commonly diagnosed cancer and the third cause of cancer death in the world, while intestinal microbiota is a community of microbes living in human intestine that can potentially impact human health in many ways. Accumulating evidence [...] Read more.

Colorectal cancer (CRC) is the second most commonly diagnosed cancer and the third cause of cancer death in the world, while intestinal microbiota is a community of microbes living in human intestine that can potentially impact human health in many ways. Accumulating evidence suggests that intestinal microbiota, especially that from the intestinal bacteria, play a key role in the CRC development; therefore, identification of bacteria involved in CRC development can provide new targets for the CRC diagnosis, prevention, and treatment. Over the past decade, there have been considerable advances in applying 16S rDNA sequencing data to verify associated intestinal bacteria in CRC patients; however, due to variations of individual and environment factors, these results seem to be inconsistent. In this review, we scrutinized the previous 16S rDNA sequencing data of intestinal bacteria from CRC patients, and identified twelve genera that are specifically enriched in the tumor microenvironment. We have focused on their relationship with the CRC development, and shown that some bacteria could promote CRC development, acting as foes, while others could inhibit CRC development, serving as friends, for human health. Finally, we highlighted their potential applications for the CRC diagnosis, prevention, and treatment. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression)

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