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Communication and Accessibility in the Tumor Microenvironment as a Therapeutic Target

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (20 September 2025) | Viewed by 12471

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Special Issue Editors

Dr. Gema Jiménez-González

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Guest Editor

Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Centre for Biomedical Research, University of Granada, E-18016 Granada, Spain
Interests: 3D bioprinting; bioinks; hydrogels; pathological processes; cancer; cancer stem cells; tumor microenvironment; organoids; cancer diagnosis; cancer treatment; translational research; personalized medicine; tumor-on-a-chip; metastasis-on-a-chip; organ-on-a-chip

Dr. Carmen Griñán-Lisón

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Guest Editor

Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Centre for Biomedical Research, University of Granada, E-18016 Granada, Spain
Interests: organoids; pathological processes; cancer; cancer stem cells; tumor microenvironment; cancer diagnosis; cancer treatment; translational research; personalized medicine; tumor-on-a-chip; metastasis-on-a-chip; organ-on-a-chip; 3D bioprinting; bioinks; hydrogels

Special Issue Information

Dear Colleagues,

The tumor microenvironment (TME) is a key factor that orchestrates tumor processes in different ways. The TME is constituted of cellular components comprising cancer stem cells and differentiated cancer cells, as well as stromal cells as mesenchymal stem cells, cancer-associated fibroblasts, endothelial cells, and immune system cells. There has been a tendency to simplify the TME to these aforementioned cellular components, but it also includes a complex and dynamic cellular communication network consisting of cytokines, growth factors, extracellular vesicles, miRNAs, among others, and an all-encompassing extracellular matrix (ECM). Currently, cancer therapies are advancing and are not exclusively directed at a single cell type, but rather target the entire TME complex, including cellular communication and the ECM that supports it.

This Special Issue aims to highlight the role of tumor communication and the ECM in treatment resistance, as well as being the objects of new targeted therapies. We are pleased to include original articles and reviews in this Special Issue.

Dr. Gema Jiménez-González
Dr. Carmen Griñán-Lisón
Guest Editors

Manuscript Submission Information

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Keywords

tumor microenvironment
cellular communication
tumor secretome
signaling
extracellular matrix
cancer treatment
targeted treatment

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Published Papers (5 papers)

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Research

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20 pages, 3922 KB

Open AccessArticle

Identification and Characterization of SRSF2 as a Splicing-Relevant Factor Associated with the Distribution of Membranous to Secreted PD-L1, Exemplarily Considered on Human Renal Tissue, Including Renal Cell Carcinoma

by Tim Hohmann, Urszula Hohmann, Faramarz Dehghani, Hendrik Borgmann, Olaf Grisk, Galyna Pryymachuk and Simon Jasinski-Bergner

Cancers 2025, 17(21), 3463; https://doi.org/10.3390/cancers17213463 - 28 Oct 2025

Viewed by 443

Abstract

Background: The immunomodulatory molecule PD-L1 and its immunological tolerance-mediating interaction with the PD-1 receptor on many immune effector cells represent one of the most important tumor immune checkpoint axes in antibody-based anti-tumor therapies. Furthermore, PD-L1 is subject to alternative splicing, whereby, in addition to the membrane-bound PD-L1, secreted PD-L1 is also formed as an additional splice variant. This also exerts its effects in the tumor microenvironment, even away from the actual tumor cells, and contributes additional benefits to immune evasion of the tumor. Methods: To examine the association of the splicing factor SRSF2 with the PD-L1 splicing pattern, respective SRSF2 overexpression and knockdown experiments were performed. The precise characterization of SRSF2 followed in human kidney tissue samples and RCCs, including immunofluorescence staining. The impact of the known oncogenic SRSF2 on the host cell transcriptome was further analyzed by RNA sequencing analyses in SRSF2 overexpression and knockdown experiments. Results: In this original research article, the trans splicing factor SRSF2 is identified to be associated with the shift in the alternative splicing pattern of PD-L1 towards the secreted splice variant. The impact of SRSF2 on the cellular transcriptome was demonstrated, and its involvement in the process of malignant transformation, which is obviously also directly linked to immune evasion. Discussion: The optimization of anti-tumor therapies based on monoclonal antibodies against immunomodulatory axes such as PD-1 and PD-L1, including necessary cost reductions, requires the detailed characterization of the gene expression and gene regulation of such molecules, as well as comprehensive molecular biological diagnostics of the tumor sample before putative therapy formulations, e.g., antibody panel collection. Conclusion: Thus, both the amount of PD-L1 protein produced and its splicing pattern are crucial for therapy success and for selecting the most effective therapeutic antibodies. Full article

(This article belongs to the Special Issue Communication and Accessibility in the Tumor Microenvironment as a Therapeutic Target)

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16 pages, 2819 KB

Open AccessArticle

Paracrine Activation of STAT3 Drives GM-CSF Expression in Breast Carcinoma Cells, Generating a Symbiotic Signaling Network with Breast Carcinoma-Associated Fibroblasts

by Kingsley O. Osuala, Anita Chalasani, Neha Aggarwal, Kyungmin Ji and Kamiar Moin

Cancers 2024, 16(16), 2910; https://doi.org/10.3390/cancers16162910 - 22 Aug 2024

Cited by 3 | Viewed by 1847

Abstract

This study evaluated the paracrine signaling between breast carcinoma-associated fibroblasts (CAFs) and breast cancer (BCa) cells. Resolving cell–cell communication in the BCa tumor microenvironment (TME) will aid the development of new therapeutics. Here, we utilized our patented TAME (tissue architecture and microenvironment engineering) 3D culture microphysiological system, which is a suitable pathomimetic avatar for the study of the BCa TME. We cultured in 3D BCa cells and CAFs either alone or together in cocultures and found that when cocultured, CAFs enhanced the invasive characteristics of tumor cells, as shown by increased proliferation and spread of tumor cells into the surrounding matrix. Secretome analysis from 3D cultures revealed a relatively high secretion of IL-6 by CAFs. A marked increase in the secretion of granulocyte macrophage-colony stimulating factor (GM-CSF) when carcinoma cells and CAFs were in coculture was also observed. We theorized that the CAF-secreted IL-6 functions in a paracrine manner to induce GM-CSF expression and secretion from carcinoma cells. This was confirmed by evaluating the activation of STAT3 and gene expression of GM-CSF in carcinoma cells exposed to CAF-conditioned media (CAF-CM). In addition, the treatment of CAFs with BCa cell-CM yielded a brief upregulation of GM-CSF followed by a marked decrease, indicating a tightly regulated control of GM-CSF in CAFs. Secretion of IL-6 from CAFs drives the activation of STAT3 in BCa cells, which in turn drives the expression and secretion of GM-CSF. As a result, CAFs exposed to BCa cell-secreted GM-CSF upregulate inflammation-associated genes such as IL-6, IL-6R and IL-8, thereby forming a positive feedback loop. We propose that the tight regulation of GM-CSF in CAFs may be a novel regulatory pathway to target for disrupting the CAF:BCa cell symbiotic relationship. These data provide yet another piece of the cell–cell communication network governing the BCa TME. Full article

(This article belongs to the Special Issue Communication and Accessibility in the Tumor Microenvironment as a Therapeutic Target)

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14 pages, 3176 KB

Open AccessArticle

A Fibroblast-Derived Secretome Stimulates the Growth and Invasiveness of 3D Plexiform Neurofibroma Spheroids

by Kyungmin Ji, George J. Schwenkel, Raymond R. Mattingly, Harini G. Sundararaghavan, Zheng Gang Zhang and Michael Chopp

Cancers 2024, 16(14), 2498; https://doi.org/10.3390/cancers16142498 - 9 Jul 2024

Cited by 4 | Viewed by 4734

Abstract

Plexiform neurofibromas (PNs) occur in about a half of neurofibromatosis type 1 (NF1) patients and have garnered significant research attention due to their capacity for growth and potential for malignant transformation. NF1 plexiform neurofibroma (pNF1) is a complex tumor composed of Schwann cell-derived tumor cells (Nf1^−/−) and the tumor microenvironment (TME). Although it has been widely demonstrated that the TME is involved in the formation of neurofibromas, little is known about the effects of the TME on the subsequent progression of human pNF1. Elucidating the molecular interactions between tumor cells and the TME may provide new therapeutic targets to reduce the progression of pNF1. In the present study, we focused on the contributions of fibroblasts, the most abundant cell types in the TME, to the growth of pNF1. To simulate the TME, we used a three-dimensional (3D) coculture model of immortalized pNF1 tumor cells (Nf1^−/−) and primary fibroblasts (Nf1^+/−) derived from pNF1 patients. We performed live-cell imaging of 3D/4D (3D in real-time) cultures through confocal microscopy followed by 3D quantitative analyses using advanced imaging software. The growth of pNF1 spheroids in 3D cocultures with fibroblasts was significantly greater than that of pNF1 spheroids in 3D monocultures. An increase in the growth of pNF1 spheroids also occurred when they were cultured with conditioned media (CM) from fibroblasts. Moreover, fibroblast-derived CM increased the invasive outgrowth and further local invasion of pNF1 spheroids. Interestingly, when small extracellular vesicles (sEVs) were depleted from the fibroblast-derived CM, the stimulation of the growth of pNF1 spheroids was lost. Our results suggest that fibroblast-derived sEVs are a therapeutic target for reducing the growth of pNF1. Full article

(This article belongs to the Special Issue Communication and Accessibility in the Tumor Microenvironment as a Therapeutic Target)

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Review

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48 pages, 3688 KB

Open AccessReview

The Role of Porphyromonas gingivalis in Oral Carcinogenesis and Progression by Remodelling the Tumour Microenvironment: A Narrative Review

by Katarzyna Starska-Kowarska

Cancers 2025, 17(21), 3478; https://doi.org/10.3390/cancers17213478 - 29 Oct 2025

Viewed by 771

Abstract

(1) Background: Oral squamous cell carcinoma (OSCC) is the most common type of head and neck malignancy worldwide. Despite the prevalence of modern diagnostic and prognostic techniques, late diagnosis and resistance to treatment still result in a low 5-year survival rate, high recurrence rate, and frequent malignant metastases. Increasing evidence indicates that bacteria of the oral microbiome, such as the Gram-negative anaerobic Porphyromonas gingivalis, may play a crucial role in the initiation and development of OSCC by inducing periodontitis. Indeed, epithelial-to-mesenchymal transition (EMT) and dysregulated immune response have been attributed to the activity of a dysbiotic microbiota. This comprehensive review examines the influence of P. gingivalis on oral carcinogenesis and progression, which has been associated with tumour microenvironment remodelling and the dysregulation of key signalling pathways related to epithelial-to-mesenchymal transition (EMT), cell-cycling, autophagy, and apoptosis. (2) Methods: The article reviews current literature on the possible role of P. gingivalis and induced dysbiosis, periodontitis and a pro-inflammatory environment as key mechanisms driving neoplastic epithelial changes and chemoresistance to anticancer agents in patients with OSCC; the research corpus was acquired from the Pub-Med/Medline/EMBASE/Cochrane Library databases. (3) Results: The identification of virulence factors and key mechanisms used by P. gingivalis to promote the development and progression of OSCC may support traditional diagnostic methods and factors related to treatment response and prevention of OSCC. (4) Conclusions: Emerging evidence suggests a possible association between periodontal bacteria and oral carcinogenesis. P. gingivalis may be an important potential target for future strategies aimed at treating oral cancer. Full article

(This article belongs to the Special Issue Communication and Accessibility in the Tumor Microenvironment as a Therapeutic Target)

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14 pages, 879 KB

Open AccessReview

Current Evidence on the Relation Between Microbiota and Oral Cancer—The Role of Fusobacterium nucleatum—A Narrative Review

by Federica Chiscuzzu, Claudia Crescio, Simona Varrucciu, Davide Rizzo, Michela Sali, Giovanni Delogu and Francesco Bussu

Cancers 2025, 17(2), 171; https://doi.org/10.3390/cancers17020171 - 7 Jan 2025

Cited by 5 | Viewed by 3750

Abstract

Oral squamous cell carcinoma (OSCC) is one the most prevalent head and neck cancers and represents a major cause of morbidity and mortality worldwide. The main established risk factors for OSCC include tobacco and alcohol consumption and betel quid chewing, which may contribute alone or in combination with other environmental factors to carcinogenesis. The oral microbiota is emerging as a key player in the establishment of the molecular and cellular mechanisms that may trigger or promote carcinogenesis, including in the oral cavity. Among the bacterial species found in the oral microbiota, Fusobacterium nucleatum, an anaerobic bacterium commonly found in oral biofilms and a periodontal pathogen, has gained attention due to solid evidence implicating F. nucleatum in colorectal cancer (CRC). F. nucleatum has been shown to induce chronic inflammation, promote cell proliferation and trigger cellular invasion while deploying immune evasion mechanisms. These experimental findings were first obtained in in vitro and in vivo models of CRC and are being confirmed in studies on OSCC. In this review, we summarize the most recent findings on the role of F. nucleatum in OSCC, discuss the clinical implications in terms of prognosis and provide an overview of the key mechanisms involved. Moreover, we identify research questions and aspects that require investigations to clarify the role of F. nucleatum in OSCC. We anticipate that studies in this emerging field may have a significant clinical impact on the diagnosis, prognosis and management of OSCC. Full article

(This article belongs to the Special Issue Communication and Accessibility in the Tumor Microenvironment as a Therapeutic Target)

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