The Role of Host Cells in Tumor Progression, Metastasis, and Therapy Response

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

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 10662

Special Issue Editor

Department of Biosciences and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
Interests: pro/anti-inflammatory molecules; cancer progression and metastasis; CXCL12

Special Issue Information

Dear Colleagues, 

Solid tumor microenvironment (TME) coevolves with the progressing tumor. Beside tumor cells, TME contains a variety of host cells, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), endothelial cells, and immune cells. Progressing tumor hijacks host cells to acquire invasive and metastatic properties and develop resistance to existing therapies. Tumor-educated host cells support tumor growth by secreting growth factors, promote tumor invasion by degrading the surrounding extracellular matrix, and facilitate metastasis by making the blood vessels leaky and escorting tumor cells into the blood. Host immune and inflammatory cells not only protect the tumor cells that are migrated into the blood circulation, but also help them seed into the secondary metastatic organs. Host cells, including CAFs, TAMs, and MDSCs have also been implicated in the development of immunosuppressive TME that support tumor growth and metastasis. Based on these pro-tumor functions, molecularly reprogramming the host cells to rather target tumor cells is being considered as an emerging therapeutic strategy. Recent clinical and pre-clinical studies using molecular checkpoint inhibitors have shown the possibility of reprogramming different immune cell types, including TAMs and T cells against tumor cells. However, tumor cells develop resistance to these therapies and other traditional therapies. Therefore, a better understanding of intricate molecular interactions between tumor and host cells is critical to design novel and efficient therapeutic strategies against solid tumors.

Dr. Dinesh Ahirwar
Guest Editor

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Published Papers (4 papers)

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Research

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14 pages, 2648 KiB  
Article
The Influence of the Ketogenic Diet on the Immune Tolerant Microenvironment in Glioblastoma
by Pravin Kesarwani, Shiva Kant, Yi Zhao, C. Ryan Miller and Prakash Chinnaiyan
Cancers 2022, 14(22), 5550; https://doi.org/10.3390/cancers14225550 - 11 Nov 2022
Cited by 5 | Viewed by 2248
Abstract
Glioblastoma (GBM) represents an aggressive and immune-resistant cancer. Preclinical investigations have identified anti-tumor activity of a ketogenic diet (KD) potentially being used to target GBM’s glycolytic phenotype. Since immune cells in the microenvironment have a similar reliance upon nutrients to perform their individual [...] Read more.
Glioblastoma (GBM) represents an aggressive and immune-resistant cancer. Preclinical investigations have identified anti-tumor activity of a ketogenic diet (KD) potentially being used to target GBM’s glycolytic phenotype. Since immune cells in the microenvironment have a similar reliance upon nutrients to perform their individual functions, we sought to determine if KD influenced the immune landscape of GBM. Consistent with previous publications, KD improved survival in GBM in an immune-competent murine model. Immunophenotyping of tumors identified KD-influenced macrophage polarization, with a paradoxical 50% increase in immune-suppressive M2-like-macrophages and a decrease in pro-inflammatory M1-like-macrophages. We recapitulated KD in vitro using a modified cell culture based on metabolomic profiling of serum in KD-fed mice, mechanistically linking the observed changes in macrophage polarization to PPARγ-activation. We hypothesized that parallel increases in M2-macrophage polarization tempered the therapeutic benefit of KD in GBM. To test this, we performed investigations combining KD with the CSF-1R inhibitor (BLZ945), which influences macrophage polarization. The combination demonstrated a striking improvement in survival and correlative studies confirmed BLZ945 normalized KD-induced changes in macrophage polarization. Overall, KD demonstrates antitumor activity in GBM; however, its efficacy is attenuated by promoting an immunosuppressive phenotype in macrophages. Combinatorial strategies designed to modulate macrophage polarization represent a rational approach to improve the anti-tumor activity of KD in GBM. Full article
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Review

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27 pages, 2240 KiB  
Review
Promises of Protein Kinase Inhibitors in Recalcitrant Small-Cell Lung Cancer: Recent Scenario and Future Possibilities
by Aniket Tiwari, Beauty Kumari, Srividhya Nandagopal, Amit Mishra, Kamla Kant Shukla, Ashok Kumar, Naveen Dutt and Dinesh Kumar Ahirwar
Cancers 2024, 16(5), 963; https://doi.org/10.3390/cancers16050963 - 27 Feb 2024
Viewed by 532
Abstract
SCLC is refractory to conventional therapies; targeted therapies and immunological checkpoint inhibitor (ICI) molecules have prolonged survival only marginally. In addition, ICIs help only a subgroup of SCLC patients. Different types of kinases play pivotal roles in therapeutics-driven cellular functions. Therefore, there is [...] Read more.
SCLC is refractory to conventional therapies; targeted therapies and immunological checkpoint inhibitor (ICI) molecules have prolonged survival only marginally. In addition, ICIs help only a subgroup of SCLC patients. Different types of kinases play pivotal roles in therapeutics-driven cellular functions. Therefore, there is a significant need to understand the roles of kinases in regulating therapeutic responses, acknowledge the existing knowledge gaps, and discuss future directions for improved therapeutics for recalcitrant SCLC. Here, we extensively review the effect of dysregulated kinases in SCLC. We further discuss the pharmacological inhibitors of kinases used in targeted therapies for recalcitrant SCLC. We also describe the role of kinases in the ICI-mediated activation of antitumor immune responses. Finally, we summarize the clinical trials evaluating the potential of kinase inhibitors and ICIs. This review overviews dysregulated kinases in SCLC and summarizes their potential as targeted therapeutic agents. We also discuss their clinical efficacy in enhancing anticancer responses mediated by ICIs. Full article
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19 pages, 2959 KiB  
Review
Development and Challenges of Diclofenac-Based Novel Therapeutics: Targeting Cancer and Complex Diseases
by Ayeman Amanullah, Arun Upadhyay, Rohan Dhiman, Sarika Singh, Amit Kumar, Dinesh Kumar Ahirwar, Ravi Kumar Gutti and Amit Mishra
Cancers 2022, 14(18), 4385; https://doi.org/10.3390/cancers14184385 - 09 Sep 2022
Cited by 15 | Viewed by 4878
Abstract
Diclofenac is a highly prescribed non-steroidal anti-inflammatory drug (NSAID) that relieves inflammation, pain, fever, and aches, used at different doses depending on clinical conditions. This drug inhibits cyclooxygenase-1 and cyclooxygenase-2 enzymes, which are responsible for the generation of prostaglandin synthesis. To improve current [...] Read more.
Diclofenac is a highly prescribed non-steroidal anti-inflammatory drug (NSAID) that relieves inflammation, pain, fever, and aches, used at different doses depending on clinical conditions. This drug inhibits cyclooxygenase-1 and cyclooxygenase-2 enzymes, which are responsible for the generation of prostaglandin synthesis. To improve current diclofenac-based therapies, we require new molecular systematic therapeutic approaches to reduce complex multifactorial effects. However, the critical challenge that appears with diclofenac and other drugs of the same class is their side effects, such as signs of stomach injuries, kidney problems, cardiovascular issues, hepatic issues, and diarrhea. In this article, we discuss why defining diclofenac-based mechanisms, pharmacological features, and its medicinal properties are needed to direct future drug development against neurodegeneration and imperfect ageing and to improve cancer therapy. In addition, we describe various advance molecular mechanisms and fundamental aspects linked with diclofenac which can strengthen and enable the better designing of new derivatives of diclofenac to overcome critical challenges and improve their applications. Full article
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26 pages, 1978 KiB  
Review
Tumour Derived Extracellular Vesicles: Challenging Target to Blunt Tumour Immune Evasion
by Tatiana Lopatina, Alessandro Sarcinella and Maria Felice Brizzi
Cancers 2022, 14(16), 4020; https://doi.org/10.3390/cancers14164020 - 20 Aug 2022
Cited by 6 | Viewed by 2539
Abstract
Control of the immune response is crucial for tumour onset and progression. Tumour cells handle the immune reaction by means of secreted factors and extracellular vesicles (EV). Tumour-derived extracellular vesicles (TEV) play key roles in immune reprogramming by delivering their cargo to different [...] Read more.
Control of the immune response is crucial for tumour onset and progression. Tumour cells handle the immune reaction by means of secreted factors and extracellular vesicles (EV). Tumour-derived extracellular vesicles (TEV) play key roles in immune reprogramming by delivering their cargo to different immune cells. Tumour-surrounding tissues also contribute to tumour immune editing and evasion, tumour progression, and drug resistance via locally released TEV. Moreover, the increase in circulating TEV has suggested their underpinning role in tumour dissemination. This review brings together data referring to TEV-driven immune regulation and antitumour immune suppression. Attention was also dedicated to TEV-mediated drug resistance. Full article
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