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Cancers
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The Tumor Microenvironment and Its Role in Tumor Growth and...
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The Tumor Microenvironment and Its Role in Tumor Growth and Angiogenesis

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

Deadline for manuscript submissions: 15 April 2025 | Viewed by 13501

Special Issue Editor

Dr. Roberto Tamma

E-Mail Website
Guest Editor
Department of Translational Biomedicine and Neuroscience (DiBraiN), Section of Human Anatomy and Histology, University of Bari Medical School Bari, 70124 Bari, Italy
Interests: angiogenesis; tumor microenvironment

Special Issue Information

Dear Colleagues,

The tumor microenvironment (TME) is a complex biological structure composed of tumor cells, endothelial cells, immune cells, fibroblasts, macrophages, and the extracellular matrix surrounding or infiltrating tumor tissues, as well as soluble substances such as cytokines and growth factors secreted by these cells. TME plays a significant role in the control of the angiogenic process, tumor growth, and metastasis. Additionally, the nature of the TME has a significant impact on the effectiveness of therapeutic interventions. Through the management of various TME components, ranging from inhibitors of angiogenic cytokines and their receptors to the regulation of cells' activities and the emerging immune checkpoint inhibitors, several processes that are useful as molecular-targeted therapeutics have been discovered. Given that the mechanisms of tumor evasion and resistance typically lower the efficiency of these novel treatment modalities, they are now a key area of research.

Dr. Roberto Tamma
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 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.

Keywords

  • tumor microenvironment
  • tumor angiogenesis
  • tumor targeted therapies
  • inflammation
  • immunotherapies

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Published Papers (7 papers)

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Research

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15 pages, 6243 KiB  
Article
From Tumor Macroenvironment to Tumor Microenvironment: The Prognostic Role of the Immune System in Oral and Lung Squamous Cell Carcinoma
by Rosa Alessia Battista, Giacomo Maria Pini, Alex Finco, Filippo Corso, Andrea Galli, Gianluigi Arrigoni, Claudio Doglioni, Marcella Callea, Matteo Paccagnella, Luca Porcu, Federica Filipello, Marco Mazzola, Giorgia Foggetti, Vanesa Gregorc, Leone Giordano, Mario Bussi, Aurora Mirabile and Giulia Veronesi
Cancers 2024, 16(15), 2759; https://doi.org/10.3390/cancers16152759 - 3 Aug 2024
Viewed by 908
Abstract
Background: The interplay between cancer cells and the immune system is crucial in cancer progression and treatment. In this regard, the tumor immune microenvironment and macroenvironment, marked by systemic inflammation markers and TILs, could be considered key prognostic factors in tumors, including oral [...] Read more.
Background: The interplay between cancer cells and the immune system is crucial in cancer progression and treatment. In this regard, the tumor immune microenvironment and macroenvironment, marked by systemic inflammation markers and TILs, could be considered key prognostic factors in tumors, including oral and lung squamous cell carcinoma. Methods: We conducted a retrospective clinical study on patients with Oral Squamous Cell Carcinoma (OSCC) and Lung Squamous Cell Carcinoma (LUSCC), examining stages, comorbidities, treatments, and outcomes. We evaluated the prognostic significance of pre-surgical systemic inflammation markers and tumor microenvironment composition. Results: Associations were found between systemic inflammation markers—NLR, MLR, and PLR—and tumor microenvironment factors, such as TILs and CD8+ cell prevalence—elevated inflammation markers correlated with advanced stages. Specifically, NLR was prognostic in OSCC, whereas PLR was prognostic in LUSCC. Using a cutoff value, we divided our tumor samples into two prognostic groups. Moreover, TILs levels >15% of tumor stroma correlated with prolonged overall survival in both OSCC and LUSCC, while increased CD8+ expression was linked to extended disease-free survival in LUSCC. Discussion: Systemic inflammation markers and TILs can be valuable prognostic factors of survival, highlighting the immune response’s role in OSCC and LUSCC. Despite limited clinical integration of the presented cohorts due to a lack of standardization, we concluded that analyzing tumor immune profiles may offer novel prognostic insights. Conclusions: Future integration into cancer classification could improve risk stratification and treatment guidance. Full article
(This article belongs to the Special Issue The Tumor Microenvironment and Its Role in Tumor Growth and Angiogenesis)
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23 pages, 11079 KiB  
Article
Serum Interleukins 8, 17, and 33 as Potential Biomarkers of Colon Cancer
by Constantin-Dan Tâlvan, Liviuța Budișan, Elena-Teodora Tâlvan, Valentin Grecu, Oana Zănoagă, Cosmin Mihalache, Victor Cristea, Ioana Berindan-Neagoe and Călin Ilie Mohor
Cancers 2024, 16(4), 745; https://doi.org/10.3390/cancers16040745 - 10 Feb 2024
Cited by 3 | Viewed by 1474
Abstract
This research investigated the serum levels of three interleukins (IL8, IL17A, and IL33) and the possible relationships between them in healthy people and colon cancer patients at different stages. This study involved 82 participants, 42 of whom had colon cancer and 40 were [...] Read more.
This research investigated the serum levels of three interleukins (IL8, IL17A, and IL33) and the possible relationships between them in healthy people and colon cancer patients at different stages. This study involved 82 participants, 42 of whom had colon cancer and 40 were healthy individuals. The cancer patients were classified into four groups according to the TNM staging classification of colon and rectal cancer. Serum levels of the interleukins were measured by the ELISA test. The data were analyzed statistically to compare the demographic characteristics, the interleukin levels across cancer stages, and the correlation between interleukins in both groups. The results showed that women had more early-stage colon cancer diagnoses, while men had more advanced-stage cancer diagnoses. Stage two colon cancer was more common in older people. Younger people, men, and those with early-stage colon cancer had higher levels of interleukins. The levels of IL8 and IL17A were higher in the cancer group, while the level of IL33 was higher in the healthy group. There was a strong correlation between IL8 and IL17A levels in both groups (p = 0.001). IL17A influenced the level of IL33 in the cancer group (p = 0.007). This study suggested that cytokine variation profiles could be useful for detecting colon cancer and predicting its outcome. Full article
(This article belongs to the Special Issue The Tumor Microenvironment and Its Role in Tumor Growth and Angiogenesis)
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10 pages, 4194 KiB  
Article
The Matrix Stiffness Coordinates the Cell Proliferation and PD-L1 Expression via YAP in Lung Adenocarcinoma
by Yeonhee Park, Dahye Lee, Jeong Eun Lee, Hee Sun Park, Sung Soo Jung, Dongil Park, Da Hyun Kang, Song-I Lee, Seong-Dae Woo and Chaeuk Chung
Cancers 2024, 16(3), 598; https://doi.org/10.3390/cancers16030598 - 31 Jan 2024
Cited by 7 | Viewed by 1962
Abstract
The extracellular matrix (ECM) exerts physiological activity, facilitates cell-to-cell communication, promotes cell proliferation and metastasis, and provides mechanical support for tumor cells. The development of solid tumors is often associated with increased stiffness. A stiff ECM promotes mechanotransduction, and the predominant transcription factors [...] Read more.
The extracellular matrix (ECM) exerts physiological activity, facilitates cell-to-cell communication, promotes cell proliferation and metastasis, and provides mechanical support for tumor cells. The development of solid tumors is often associated with increased stiffness. A stiff ECM promotes mechanotransduction, and the predominant transcription factors implicated in this phenomenon are YAP/TAZ, β-catenin, and NF-κB. In this study, we aimed to investigate whether YAP is a critical mediator linking matrix stiffness and PD-L1 in lung adenocarcinoma. We confirmed that YAP, PD-L1, and Ki-67, a marker of cell proliferation, increase as the matrix stiffness increases in vitro using the lung adenocarcinoma cell lines PC9 and HCC827 cells. The knockdown of YAP decreased the expression of PD-L1 and Ki-67, and conversely, the overexpression of YAP increased the expression of PD-L1 and K-67 in a stiff-matrix environment (20.0 kPa). Additionally, lung cancer cells were cultured in a 3D environment, which provides a more physiologically relevant setting, and compared to the results obtained from 2D culture. Similar to the findings in 2D culture, it was confirmed that YAP influenced the expression of PD-L1 and K-67 in the 3D culture experiment. Our results suggest that matrix stiffness controls PD-L1 expression via YAP activation, ultimately contributing to cell proliferation. Full article
(This article belongs to the Special Issue The Tumor Microenvironment and Its Role in Tumor Growth and Angiogenesis)
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16 pages, 2290 KiB  
Article
Interleukin-6 Induces Stem Cell Propagation through Liaison with the Sortilin–Progranulin Axis in Breast Cancer
by Karoline Berger, Emma Persson, Pernilla Gregersson, Santiago Ruiz-Martínez, Emma Jonasson, Anders Ståhlberg, Sara Rhost and Göran Landberg
Cancers 2023, 15(24), 5757; https://doi.org/10.3390/cancers15245757 - 8 Dec 2023
Cited by 2 | Viewed by 1590
Abstract
Unraveling the complex network between cancer cells and their tumor microenvironment is of clinical importance, as it might allow for the identification of new targets for cancer treatment. Cytokines and growth factors secreted by various cell types present in the tumor microenvironment have [...] Read more.
Unraveling the complex network between cancer cells and their tumor microenvironment is of clinical importance, as it might allow for the identification of new targets for cancer treatment. Cytokines and growth factors secreted by various cell types present in the tumor microenvironment have the potential to affect the challenging subpopulation of cancer stem cells showing treatment-resistant properties as well as aggressive features. By using various model systems, we investigated how the breast cancer stem cell-initiating growth factor progranulin influenced the secretion of cancer-associated proteins. In monolayer cultures, progranulin induced secretion of several inflammatory-related cytokines, such as interleukin (IL)-6 and -8, in a sortilin-dependent manner. Further, IL-6 increased the cancer stem fraction similarly to progranulin in the breast cancer cell lines MCF7 and MDA-MB-231 monitored by the surrogate mammosphere-forming assay. In a cohort of 63 patient-derived scaffold cultures cultured with breast cancer cells, we observed significant correlations between IL-6 and progranulin secretion, clearly validating the association between IL-6 and progranulin also in human-based microenvironments. In conclusion, the interplay between progranulin and IL-6 highlights a dual breast cancer stem cell-promoting function via sortilin, further supporting sortilin as a highly relevant therapeutic target for aggressive breast cancer. Full article
(This article belongs to the Special Issue The Tumor Microenvironment and Its Role in Tumor Growth and Angiogenesis)
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10 pages, 1059 KiB  
Communication
Vascular Growth in Lymphomas: Angiogenesis and Alternative Ways
by Domenico Ribatti, Roberto Tamma, Tiziana Annese, Antonio d’Amati, Giuseppe Ingravallo and Giorgina Specchia
Cancers 2023, 15(12), 3262; https://doi.org/10.3390/cancers15123262 - 20 Jun 2023
Cited by 6 | Viewed by 1651
Abstract
The formation of new blood vessels is a critical process for tumor growth and may be achieved through different mechanisms. Angiogenesis represents the first described and most studied mode of vessel formation, but tumors may also use alternative ways to secure blood supply [...] Read more.
The formation of new blood vessels is a critical process for tumor growth and may be achieved through different mechanisms. Angiogenesis represents the first described and most studied mode of vessel formation, but tumors may also use alternative ways to secure blood supply and eventually acquire resistance to anti-angiogenic treatments. These non-angiogenic mechanisms have been described more recently, including intussusceptive microvascular growth (IMG), vascular co-option, and vasculogenic mimicry. Like solid tumors, angiogenic and non-angiogenic pathways in lymphomas play a fundamental role in tumor growth and progression. In view of the relevant prognostic and therapeutic implications, a comprehensive understanding of these mechanisms is of paramount importance for improving the efficacy of treatment in patients with lymphoma. In this review, we summarize the current knowledge on angiogenic and non-angiogenic mechanisms involved in the formation of new blood vessels in Hodgkin’s and non-Hodgkin’s lymphomas. Full article
(This article belongs to the Special Issue The Tumor Microenvironment and Its Role in Tumor Growth and Angiogenesis)
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13 pages, 17283 KiB  
Article
The Tumor Microenvironment in Classic Hodgkin’s Lymphoma in Responder and No-Responder Patients to First Line ABVD Therapy
by Roberto Tamma, Giuseppe Ingravallo, Francesco Gaudio, Antonio d’Amati, Pierluigi Masciopinto, Emilio Bellitti, Loredana Lorusso, Tiziana Annese, Vincenzo Benagiano, Pellegrino Musto, Giorgina Specchia and Domenico Ribatti
Cancers 2023, 15(10), 2803; https://doi.org/10.3390/cancers15102803 - 17 May 2023
Cited by 7 | Viewed by 1798
Abstract
Although classical Hodgkin lymphoma (CHL) is typically curable, 15–25% of individuals eventually experience a relapse and pass away from their disease. In CHL, the cellular microenvironment is constituted by few percent of H/RS (Hodgkin/Reed–Sternberg) tumor cells surrounded from a heterogeneous infiltration of inflammatory [...] Read more.
Although classical Hodgkin lymphoma (CHL) is typically curable, 15–25% of individuals eventually experience a relapse and pass away from their disease. In CHL, the cellular microenvironment is constituted by few percent of H/RS (Hodgkin/Reed–Sternberg) tumor cells surrounded from a heterogeneous infiltration of inflammatory cells. The interplay of H/RS cells with other immune cells in the microenvironment may provide novel strategies for targeted immunotherapies. In this paper we analyzed the microenvironment content in CHL patients with responsive disease (RESP) and patients with relapsed/refractory disease to treatment (REL). Our results indicate the increase of CD68+ and CD163+ macrophages, the increase of PDL-1+ cells and of CD34+ microvessels in REL patients respective to RESP patients. In contrast we also found the decrease of CD3+ and of CD8+ lymphocytes in REL patients respective to RESP patients. Finally, in REL patients our results show the positive correlation between CD68+ macrophages and PDL-1+ cells as well as a negative correlation between CD163+ and CD3+. Full article
(This article belongs to the Special Issue The Tumor Microenvironment and Its Role in Tumor Growth and Angiogenesis)
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Review

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22 pages, 1156 KiB  
Review
The Role of Curcumin in Cancer: A Focus on the PI3K/Akt Pathway
by Vasiliki Zoi, Athanassios P. Kyritsis, Vasiliki Galani, Diamanto Lazari, Chrissa Sioka, Spyridon Voulgaris and Georgios A. Alexiou
Cancers 2024, 16(8), 1554; https://doi.org/10.3390/cancers16081554 - 18 Apr 2024
Cited by 12 | Viewed by 3371
Abstract
Cancer is a life-threatening disease and one of the leading causes of death worldwide. Despite significant advancements in therapeutic options, most available anti-cancer agents have limited efficacy. In this context, natural compounds with diverse chemical structures have been investigated for their multimodal anti-cancer [...] Read more.
Cancer is a life-threatening disease and one of the leading causes of death worldwide. Despite significant advancements in therapeutic options, most available anti-cancer agents have limited efficacy. In this context, natural compounds with diverse chemical structures have been investigated for their multimodal anti-cancer properties. Curcumin is a polyphenol isolated from the rhizomes of Curcuma longa and has been widely studied for its anti-inflammatory, anti-oxidant, and anti-cancer effects. Curcumin acts on the regulation of different aspects of cancer development, including initiation, metastasis, angiogenesis, and progression. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway is a key target in cancer therapy, since it is implicated in initiation, proliferation, and cancer cell survival. Curcumin has been found to inhibit the PI3K/Akt pathway in tumor cells, primarily via the regulation of different key mediators, including growth factors, protein kinases, and cytokines. This review presents the therapeutic potential of curcumin in different malignancies, such as glioblastoma, prostate and breast cancer, and head and neck cancers, through the targeting of the PI3K/Akt signaling pathway. Full article
(This article belongs to the Special Issue The Tumor Microenvironment and Its Role in Tumor Growth and Angiogenesis)
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