ijms-logo

Journal Browser

Journal Browser

Microenvironment in Cancer Progression and Metastases: Crosstalk between Cancer Cells and Microenvironment

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 April 2020) | Viewed by 38512

Special Issue Editor

Multidisciplinary Oncology Centre Antwerp (MOCA), Universitair Ziekenhuis Antwerpen, 2650 Edegem, Belgium
Interests: translational research; breast cancer; inflammatory breast cancer; cervical cancer; targeted treatment; biomarkers; liquid biopsies

Special Issue Information

Dear Colleagues,

Over the last decades evidence has accumulated showing that crosstalk between cancer cells and the microenvironment plays an important role in tumor initiation, progression, and metastatasis. Novel targeted treatments and immune therapies have emerged specifically focusing on altering the interaction between tumor cells stroma, immune cells, and vasculature. In the current series, we invite papers dealing with the basic research, translational research, and clinical studies on the interaction between the tumor cells and their microenvironment.

Prof. Dr. Peter van Dam
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • cancer
  • microenvironment
  • stroma
  • immune response
  • targeted treatment

Published Papers (9 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

13 pages, 1551 KiB  
Article
Fibroblasts as a Biological Marker for Curative Resection in Pancreatic Ductal Adenocarcinoma
by Eriko Katsuta, Omar M. Rashid and Kazuaki Takabe
Int. J. Mol. Sci. 2020, 21(11), 3890; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113890 - 29 May 2020
Cited by 26 | Viewed by 2383
Abstract
Achievement of microscopic tumor clearance (R0) after pancreatic ductal adenocarcinoma (PDAC) surgery is determined by cancer biology rather than operative technique. Fibroblasts are known to play pro-cancer roles; however, a small subset was recently found to play anti-cancer roles. Therefore, we hypothesized that [...] Read more.
Achievement of microscopic tumor clearance (R0) after pancreatic ductal adenocarcinoma (PDAC) surgery is determined by cancer biology rather than operative technique. Fibroblasts are known to play pro-cancer roles; however, a small subset was recently found to play anti-cancer roles. Therefore, we hypothesized that intratumor fibroblasts contribute to curative resection and a better survival of PDAC. Utilizing a large, publicly available PDAC cohort, we found that fibroblast composition was associated with R0 curative resection. A high amount of fibroblasts in PDACs was significantly associated with a higher amount of mature vessels, but not with blood angiogenesis. A high amount of fibroblasts was also associated with a higher infiltration of anti-cancer immune cells, such as CD8+ T-cells and dendritic cells, together with higher inflammatory signaling, including IL2/STAT5 and IL6/JAK/STAT3 signaling. Further, the fibroblast composition was inversely associated with cancer cell composition in the bulk tumor, along with an inverse association with proliferative characteristics, such as MYC signaling and glycolysis. The patients with high-fibroblast PDACs showed an improved prognosis. In conclusion, we found that PDACs with high fibroblasts were associated with a higher R0 resection rate, resulting in a better prognosis. These findings may be due to less aggressive biology with a higher vascularity and anti-cancer immunity, and a low cancer cell component. Full article
Show Figures

Figure 1

18 pages, 1905 KiB  
Article
Calcium Channels as Novel Therapeutic Targets for Ovarian Cancer Stem Cells
by Heejin Lee, Jun Woo Kim, Dae Kyung Kim, Dong Kyu Choi, Seul Lee, Ji Hoon Yu, Oh-Bin Kwon, Jungsul Lee, Dong-Seok Lee, Jae Ho Kim and Sang-Hyun Min
Int. J. Mol. Sci. 2020, 21(7), 2327; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072327 - 27 Mar 2020
Cited by 34 | Viewed by 3588
Abstract
Drug resistance in epithelial ovarian cancer (EOC) is reportedly attributed to the existence of cancer stem cells (CSC), because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers [...] Read more.
Drug resistance in epithelial ovarian cancer (EOC) is reportedly attributed to the existence of cancer stem cells (CSC), because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells (CSCs). We screened an FDA-approved compound library and found four voltage-gated calcium channel blockers (manidipine, lacidipine, benidipine, and lomerizine) that target ovarian CSCs. Four calcium channel blockers (CCBs) decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. CCBs destroyed stemness and inhibited the AKT and ERK signaling pathway in ovarian CSCs. Among calcium channel subunit genes, three L- and T-type calcium channel genes were overexpressed in ovarian CSCs, and downregulation of calcium channel genes reduced the stem-cell-like properties of ovarian CSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with cisplatin, synergistic effect was shown in inhibiting the viability and proliferation of ovarian CSCs. Moreover, combinatorial usage of manidipine and paclitaxel showed enhanced effect in ovarian CSCs xenograft mouse models. Our results suggested that four CCBs may be potential therapeutic drugs for preventing ovarian cancer recurrence. Full article
Show Figures

Figure 1

16 pages, 2292 KiB  
Article
Tumor-Stroma Crosstalk Enhances REG3A Expressions that Drive the Progression of Hepatocellular Carcinoma
by Yuri Cho, Min Ji Park, Koeun Kim, Jae-Young Park, Jihye Kim, Wonjin Kim and Jung-Hwan Yoon
Int. J. Mol. Sci. 2020, 21(2), 472; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020472 - 11 Jan 2020
Cited by 10 | Viewed by 2761
Abstract
Abstract: Background: Crosstalk between tumors and their microenvironment plays a crucial role in the progression of hepatocellular carcinoma (HCC). However, there is little existing information about the key signaling molecule that modulates tumor-stroma crosstalk. Methods: Complementary DNA (cDNA) microarray analysis was performed to [...] Read more.
Abstract: Background: Crosstalk between tumors and their microenvironment plays a crucial role in the progression of hepatocellular carcinoma (HCC). However, there is little existing information about the key signaling molecule that modulates tumor-stroma crosstalk. Methods: Complementary DNA (cDNA) microarray analysis was performed to identify the key molecule in tumor-stroma crosstalk. Subcutaneous xenograft in vivo murine model, immunoblotting, immunofluorescence, and real-time polymerase chain reaction using HCC cells and tissues were performed. Results: The key molecule, regenerating gene protein-3A (REG3A), was most significantly enhanced when coculturing HCC cells and activated human hepatic stellate cells (HSCs) (+8.2 log) compared with monoculturing HCC cells using cDNA microarray analysis. Downregulation of REG3A using small interfering RNA significantly decreased the proliferation of HSC-cocultured HCC cells in vitro and in vivo, and enhanced deoxycholic acid-induced HCC cell apoptosis. Crosstalk-induced REG3A upregulation was modulated by platelet-derived growth factor ββ (PDGF-ββ) in p42/44-dependent manner. REG3A mRNA levels in human HCC tissues were upregulated 1.8-fold compared with non-tumor tissues and positively correlated with PDGF-ββ levels. Conclusions: REG3A/p42/44 pathway/PDGF-ββ signaling plays a significant role in hepatocarcinogenesis via tumor-stroma crosstalk. Targeting REG3A is a potential novel therapeutic target for the management of HCCs by inhibiting crosstalk between HCC cells and HSCs. Full article
Show Figures

Figure 1

14 pages, 6454 KiB  
Article
Small Extracellular Vesicles Released from Ovarian Cancer Spheroids in Response to Cisplatin Promote the Pro-Tumorigenic Activity of Mesenchymal Stem Cells
by Nelly Vera, Stephanie Acuña-Gallardo, Felipe Grünenwald, Albano Caceres-Verschae, Ornella Realini, Rodrigo Acuña, Alvaro Lladser, Sebastián E. Illanes and Manuel Varas-Godoy
Int. J. Mol. Sci. 2019, 20(20), 4972; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20204972 - 09 Oct 2019
Cited by 24 | Viewed by 4639
Abstract
Despite the different strategies used to treat ovarian cancer, around 70% of women/patients eventually fail to respond to the therapy. Cancer stem cells (CSCs) play a role in the treatment failure due to their chemoresistant properties. This capacity to resist chemotherapy allows CSCs [...] Read more.
Despite the different strategies used to treat ovarian cancer, around 70% of women/patients eventually fail to respond to the therapy. Cancer stem cells (CSCs) play a role in the treatment failure due to their chemoresistant properties. This capacity to resist chemotherapy allows CSCs to interact with different components of the tumor microenvironment, such as mesenchymal stem cells (MSCs), and thus contribute to tumorigenic processes. Although the participation of MSCs in tumor progression is well understood, it remains unclear how CSCs induce the pro-tumorigenic activity of MSCs in response to chemotherapy. Small extracellular vesicles, including exosomes, represent one possible way to modulate any type of cell. Therefore, in this study, we evaluate if small extracellular vesicle (sEV) derived from ovarian cancer spheroids (OCS), which are enriched in CSCs, can modify the activity of MSCs to a pro-tumorigenic phenotype. We show that sEV released by OCS in response to cisplatin induce an increase in the migration pattern of bone marrow MSCs (BM-MSCs) and the secretion interleukin-6 (IL-6), interleukin-8 (IL-8), and vascular endothelial growth factor A (VEGFA). Moreover, the factors secreted by BM-MSCs induce angiogenesis in endothelial cells and the migration of low-invasive ovarian cancer cells. These findings suggest that cisplatin could modulate the cargo of sEV released by CSCs, and these exosomes can further induce the pro-tumorigenic activity of MSCs. Full article
Show Figures

Figure 1

17 pages, 4375 KiB  
Article
Building a Bridge between Chemotherapy and Immunotherapy in Malignant Pleural Mesothelioma: Investigating the Effect of Chemotherapy on Immune Checkpoint Expression
by Elly Marcq, Jonas RM Van Audenaerde, Jorrit De Waele, Julie Jacobs, Jinthe Van Loenhout, Glenn Cavents, Patrick Pauwels, Jan P van Meerbeeck and Evelien LJ Smits
Int. J. Mol. Sci. 2019, 20(17), 4182; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20174182 - 26 Aug 2019
Cited by 11 | Viewed by 3195
Abstract
In light of the promising results of immune checkpoint blockade (ICPB) in malignant pleural mesothelioma (MPM), we investigated the effect of different chemotherapeutic agents on the expression of immune checkpoints (ICPs) in order to rationally design a good treatment schedule for their combination [...] Read more.
In light of the promising results of immune checkpoint blockade (ICPB) in malignant pleural mesothelioma (MPM), we investigated the effect of different chemotherapeutic agents on the expression of immune checkpoints (ICPs) in order to rationally design a good treatment schedule for their combination with ICP blocking antibodies. Cisplatin, oxaliplatin and pemetrexed are interesting chemotherapeutic agents to combine with immunotherapy given their immunomodulatory capacities. We looked into cisplatin and pemetrexed because their combination is used as first-line treatment of MPM. Additionally, the effect of the immunogenic chemotherapeutic agent, oxaliplatin, was also studied. Three different MPM cell lines were used for representation of both epithelioid and sarcomatoid subtypes. The desired inhibitory concentrations of the chemotherapeutic agents were determined with the SRB-assay. Allogeneic co-cultures of MPM cells with healthy donor peripheral blood mononuclear cells (PBMC) were set up to assess the effect of these chemotherapeutic agents on the expression of ICPs (PD-1, LAG-3, TIM-3) and their ligands (PD-L1, PD-L2, galectin-9). Cisplatin might be a promising treatment to combine with ICP blocking antibodies since our MPM cell lines were most susceptible to this stand-alone treatment. We found that the expression of ICPs and their ligands on both MPM cells and PBMC was mostly downregulated or unaltered when treated with chemotherapeutic agents, though no clear trend could be determined. Full article
Show Figures

Figure 1

12 pages, 2481 KiB  
Article
Novel Targeted Anti-Tumor Nanoparticles Developed from Folic Acid-Modified 2-Deoxyglucose
by Shaoming Jin, Zhongyao Du, Huiyuan Guo, Hao Zhang, Fazheng Ren and Pengjie Wang
Int. J. Mol. Sci. 2019, 20(3), 697; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030697 - 06 Feb 2019
Cited by 17 | Viewed by 3746
Abstract
The glucose analog, 2-deoxyglucose (2-DG), specifically inhibits glycolysis of cancer cells and interferes with the growth of cancer cells. However, the excellent water solubility of 2-DG makes it difficult to be concentrated in tumor cells. In this study, a targeted nano-pharmacosome was developed [...] Read more.
The glucose analog, 2-deoxyglucose (2-DG), specifically inhibits glycolysis of cancer cells and interferes with the growth of cancer cells. However, the excellent water solubility of 2-DG makes it difficult to be concentrated in tumor cells. In this study, a targeted nano-pharmacosome was developed with folic acid-modified 2-DG (FA-2-DG) by using amino ethanol as a cleavable linker. FA-2-DG was able to self-assemble, forming nano-particles with diameters of 10–30 nm. The biological effects were evaluated with cell viability assays and flow cytometry analysis. Compared with a physical mixture of folic acid and 2-DG, FA-2-DG clearly reduced cell viability and resulted in cell cycle arrest. A computational study involving docking simulation suggested that FA-2-DG can dock into the same receptor as folic acid, thus confirming that the structural modification did not affect the targeting performance. The results indicated that the nano-pharmacosome consisting of FA-2-DG can be used for targeting in a nano-drug delivery system. Full article
Show Figures

Figure 1

Review

Jump to: Research

22 pages, 964 KiB  
Review
The Role of Immune Checkpoints after Cellular Therapy
by Friederike Schmitz, Dominik Wolf and Tobias A.W. Holderried
Int. J. Mol. Sci. 2020, 21(10), 3650; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103650 - 21 May 2020
Cited by 6 | Viewed by 3051
Abstract
Cellular therapies utilize the powerful force of the human immune system to target malignant cells. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the most established cellular therapy, but chimeric antigen receptor (CAR) T cell therapies have gained attention in recent years. While in [...] Read more.
Cellular therapies utilize the powerful force of the human immune system to target malignant cells. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the most established cellular therapy, but chimeric antigen receptor (CAR) T cell therapies have gained attention in recent years. While in allo-HCT an entirely novel allogeneic immune system facilitates a so-called Graft-versus-tumor, respectively, Graft-versus-leukemia (GvT/GvL) effect against high-risk hematologic malignancies, in CAR T cell therapies genetically modified autologous T cells specifically attack target molecules on malignant cells. These therapies have achieved high success rates, offering potential cures in otherwise detrimental diseases. However, relapse after cellular therapy remains a serious clinical obstacle. Checkpoint Inhibition (CI), which was recently designated as breakthrough in cancer treatment and consequently awarded with the Nobel prize in 2018, is a different way to increase anti-tumor immunity. Here, inhibitory immune checkpoints are blocked on immune cells in order to restore the immunological force against malignant diseases. Disease relapse after CAR T cell therapy or allo-HCT has been linked to up-regulation of immune checkpoints that render cancer cells resistant to the cell-mediated anti-cancer immune effects. Thus, enhancing immune cell function after cellular therapies using CI is an important treatment option that might re-activate the anti-cancer effect upon cell therapy. In this review, we will summarize current data on this topic with the focus on immune checkpoints after cellular therapy for malignant diseases and balance efficacy versus potential side effects. Full article
Show Figures

Figure 1

21 pages, 3311 KiB  
Review
Tumor Dormancy and Interplay with Hypoxic Tumor Microenvironment
by Elena Butturini, Alessandra Carcereri de Prati, Diana Boriero and Sofia Mariotto
Int. J. Mol. Sci. 2019, 20(17), 4305; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20174305 - 03 Sep 2019
Cited by 74 | Viewed by 8327
Abstract
The tumor microenvironment is a key factor in disease progression, local resistance, immune-escaping, and metastasis. The rapid proliferation of tumor cells and the aberrant structure of the blood vessels within tumors result in a marked heterogeneity in the perfusion of the tumor tissue [...] Read more.
The tumor microenvironment is a key factor in disease progression, local resistance, immune-escaping, and metastasis. The rapid proliferation of tumor cells and the aberrant structure of the blood vessels within tumors result in a marked heterogeneity in the perfusion of the tumor tissue with regions of hypoxia. Although most of the tumor cells die in these hypoxic conditions, a part of them can adapt and survive for many days or months in a dormant state. Dormant tumor cells are characterized by cell cycle arrest in G0/G1 phase as well as a low metabolism, and are refractive to common chemotherapy, giving rise to metastasis. Despite these features, the cells retain their ability to proliferate when conditions improve. An understanding of the regulatory machinery of tumor dormancy is essential for identifying early cancer biomarkers and could provide a rationale for the development of novel agents to target dormant tumor cell populations. In this review, we examine the current knowledge of the mechanisms allowing tumor dormancy and discuss the crucial role of the hypoxic microenvironment in this process. Full article
Show Figures

Figure 1

15 pages, 900 KiB  
Review
RANK-RANKL Signaling in Cancer of the Uterine Cervix: A Review
by Peter A. van Dam, Yannick Verhoeven, Julie Jacobs, An Wouters, Wiebren Tjalma, Filip Lardon, Tim Van den Wyngaert, Jonatan Dewulf, Evelien Smits, Cécile Colpaert, Hans Prenen, Marc Peeters, Martin Lammens and Xuan Bich Trinh
Int. J. Mol. Sci. 2019, 20(9), 2183; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092183 - 02 May 2019
Cited by 23 | Viewed by 6125
Abstract
RANK ligand (RANKL) is a member of the tumor necrosis factor alpha superfamily of cytokines. It is the only known ligand binding to a membrane receptor named receptor activator of nuclear factor-kappa B (RANK), thereby triggering recruitment of tumor necrosis factor (TNF) receptor [...] Read more.
RANK ligand (RANKL) is a member of the tumor necrosis factor alpha superfamily of cytokines. It is the only known ligand binding to a membrane receptor named receptor activator of nuclear factor-kappa B (RANK), thereby triggering recruitment of tumor necrosis factor (TNF) receptor associated factor (TRAF) adaptor proteins and activation of downstream pathways. RANK/RANKL signaling is controlled by a decoy receptor called osteoprotegerin (OPG), but also has additional more complex levels of regulation. The existing literature on RANK/RANKL signaling in cervical cancer was reviewed, particularly focusing on the effects on the microenvironment. RANKL and RANK are frequently co-expressed in cervical cancer cells lines and in carcinoma of the uterine cervix. RANKL and OPG expression strongly increases during cervical cancer progression. RANKL is directly secreted by cervical cancer cells, which may be a mechanism they use to create an immune suppressive environment. RANKL induces expression of multiple activating cytokines by dendritic cells. High RANK mRNA levels and high immunohistochemical OPG expression are significantly correlated with high clinical stage, tumor grade, presence of lymph node metastases, and poor overall survival. Inhibition of RANKL signaling has a direct effect on tumor cell proliferation and behavior, but also alters the microenvironment. Abundant circumstantial evidence suggests that RANKL inhibition may (partially) reverse an immunosuppressive status. The use of denosumab, a monoclonal antibody directed to RANKL, as an immunomodulatory strategy is an attractive concept which should be further explored in combination with immune therapy in patients with cervical cancer. Full article
Show Figures

Figure 1

Back to TopTop