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Advances in the Comprehension of the Molecular Basis of Cancer and New Therapeutic Strategies 2021

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 15837

Special Issue Editors


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Co-Guest Editor
Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana (AOUP), via Roma 67, 56126 Pisa, Italy
Interests: breast and gastrointestinal cancer follow-up and therapy; breast cancer biomarkers and prognostic factors; cancer immunology; circulating tumor cells; cancer stem cells
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Special Issue Information

Dear Colleagues,

Over the last two decades, a new era of molecular targeted therapies has been launched in the battle against cancer.

In these two decades, a great contribution to the comprehension of cancer has been provided by the myriad of elucidated pathological molecular pathways. Many of them were and will be the basis for the design of novel drugs and the stimulation of further investigations. Furthermore, these advances in molecular biology are the platform for genetic and epigenetic studies to better understand the origin of the discovered molecular alterations and contribute to unravelling the complexity of cancer in its advanced stages.

However, to date, while many of the novel drugs have entered into clinical practice, the expected therapeutic advances, mainly the benefit in terms of improved OS, when it occurs, have been marginal in all but a minority of patients with the common types of advanced cancer.

To overcome this deadlock, in addition to focusing on single or a few molecular pathways, it is urgent to look at the entire complexity of the system in its advanced stage. Therefore, this Special Issue focuses on molecular-level research and provides a space for new therapeutic strategies, including those based on a robust rationale, and examining the entire complexity of the system.

Prof. Dr. Andrea Nicolini
Guest Editor
Dr. Paola Ferrar
Co-Guest Editor

Manuscript Submission Information

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Keywords

  • advanced solid tumors
  • therapeutic strategies
  • tumor growth
  • immune evasion
  • anaplastic thyroid cancer
  • non-small cell lung cancer
  • liquid biopsy
  • colon cancer
  • tumor with unknown origin

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Published Papers (4 papers)

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Research

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15 pages, 2784 KiB  
Article
Overexpression of VEGF in the MOPC 315 Plasmacytoma Induces Tumor Immunity in Mice
by Byung-Gyu Kim, Sung Hee Choi, John J. Letterio, Jie-Young Song and Alex Y. Huang
Int. J. Mol. Sci. 2022, 23(9), 5235; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095235 - 07 May 2022
Cited by 1 | Viewed by 1971
Abstract
Vascular endothelial growth factor (VEGF) has important effects on hematopoietic and immune cells. A link between VEGF expression, tumor progression, and metastasis has been established in various solid tumors; however, the impact of VEGF expression by hematopoietic neoplasias remains unclear. Here, we investigated [...] Read more.
Vascular endothelial growth factor (VEGF) has important effects on hematopoietic and immune cells. A link between VEGF expression, tumor progression, and metastasis has been established in various solid tumors; however, the impact of VEGF expression by hematopoietic neoplasias remains unclear. Here, we investigated the role of VEGF in plasma cell neoplasia. Overexpression of VEGF in MOPC 315 tumor cells (MOPCSVm) had no effect on their growth in vitro. However, constitutive ectopic expression of VEGF dramatically reduced tumorigenicity of MOPC 315 when implanted subcutaneously into BALB/c mice. Mice implanted with MOPCSVm effectively rejected tumor grafts and showed strong cytotoxic T lymphocyte (CTL) activity against parental MOPC 315 cells. MOPCSVm implants were not rejected in nude mice, suggesting the process is T-cell-dependent. Adoptive transfer of splenocytes from recipients inoculated with MOPCSVm cells conferred immunity to naïve BALB/c mice, and mice surviving inoculation with MOPCSVm rejected the parental MOPC 315 tumor cells following a second inoculation. Immunohistochemical analysis showed that MOPCSVm induced a massive infiltration of CD3+ cells and MHC class II+ cells in vivo. In addition, exogenous VEGF induced the expression of CCR3 in T cells in vitro. Together, these data are the first to demonstrate that overexpression of VEGF in plasmacytoma inhibits tumor growth and enhances T-cell-mediated antitumor immune response. Full article
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Review

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12 pages, 1458 KiB  
Review
Mechanism of Extracellular Vesicle Secretion Associated with TGF-β-Dependent Inflammatory Response in the Tumor Microenvironment
by Klaudia Bonowicz, Klaudia Mikołajczyk, Inaz Faisal, Murtaz Qamar, Kerstin Steinbrink, Konrad Kleszczyński, Alina Grzanka and Maciej Gagat
Int. J. Mol. Sci. 2022, 23(23), 15335; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315335 - 05 Dec 2022
Cited by 1 | Viewed by 1704
Abstract
Extracellular vesicles (EVs) serve as central mediators in communication between tumor and non-tumor cells. These interactions are largely dependent on the function of the endothelial barrier and the set of receptors present on its surface, as endothelial cells (ECs) are a plenteous source [...] Read more.
Extracellular vesicles (EVs) serve as central mediators in communication between tumor and non-tumor cells. These interactions are largely dependent on the function of the endothelial barrier and the set of receptors present on its surface, as endothelial cells (ECs) are a plenteous source of EVs. The molecular basis for EV secretion and action in the tumor microenvironment (TME) has not been fully elucidated to date. Emerging evidence suggests a prominent role of inflammatory pathways in promoting tumor progression and metastasis. Although transforming growth factor β (TGF-β) is a cytokine with strong immunomodulatory and protective activity in benign and early-stage cancer cells, it plays a pro-tumorigenic role in advanced cancer cells, which is known as the “TGF-β paradox”. Thus, the aim of this review is to describe the correlation between EV release, TGF-β-dependent inflammation, and dysregulation of downstream TGF-β signaling in the context of cancer development. Full article
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37 pages, 1105 KiB  
Review
Molecular Mechanisms, Biomarkers and Emerging Therapies for Chemotherapy Resistant TNBC
by Paola Ferrari, Cristian Scatena, Matteo Ghilli, Irene Bargagna, Giulia Lorenzini and Andrea Nicolini
Int. J. Mol. Sci. 2022, 23(3), 1665; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031665 - 31 Jan 2022
Cited by 50 | Viewed by 7988
Abstract
Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant [...] Read more.
Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings. Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for BRCA1/2 germline mutation carriers larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase (NTRK) gene fusion carriers, and anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy for heavily pretreated metastatic TNBC (mTNBC). Further therapies targeting some pathologic molecular pathways, apoptosis, miRNAS, epidermal growth factor receptor (EGFR), insulin growth factor 1 receptor (IGF-1R), and androgen receptor (AR) are under investigation. Among them, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and EGFR inhibitors as well as antiandrogens showed promising results and are under evaluation in Phase II/III clinical trials. Emerging therapies allow to select specific antiblastics that alone or by integrating the conventional therapeutic approach may overcome/hinder chemoresistance. Full article
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15 pages, 1324 KiB  
Review
Fibroblast Growth Factor Inhibitors for Treating Locally Advanced/Metastatic Bladder Urothelial Carcinomas via Dual Targeting of Tumor-Specific Oncogenic Signaling and the Tumor Immune Microenvironment
by Hye Won Lee and Ho Kyung Seo
Int. J. Mol. Sci. 2021, 22(17), 9526; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179526 - 02 Sep 2021
Cited by 7 | Viewed by 3214
Abstract
Locally advanced or metastatic urothelial bladder cancer (a/m UBC) is currently treated using platinum-based combination chemotherapy. Immune checkpoint inhibitors (ICIs) are the preferred second-line treatment options for cisplatin-eligible a/m UBC patients and as first-line options in cisplatin-ineligible settings. However, the response rates for [...] Read more.
Locally advanced or metastatic urothelial bladder cancer (a/m UBC) is currently treated using platinum-based combination chemotherapy. Immune checkpoint inhibitors (ICIs) are the preferred second-line treatment options for cisplatin-eligible a/m UBC patients and as first-line options in cisplatin-ineligible settings. However, the response rates for ICI monotherapy are modest (~20%), which necessitates the exploration of alternative strategies. Dysregulated activation of fibroblast growth factor receptor (FGFR) signaling enhances tumor proliferation, survival, invasion, angiogenesis, and immune evasion. The recent U.S. Food and Drug Administration approval of erdafitinib and the emergence of other potent and selective FGFR inhibitors (FGFRis) have shifted the treatment paradigm for patients with a/m UBC harboring actionable FGFR2 or FGFR3 genomic alterations, who often have a minimal-to-modest response to ICIs. FGFRi–ICI combinations are therefore worth exploring, and their preliminary response rates and safety profiles are promising. In the present review, we summarize the impact of altered FGFR signaling on a/m UBC tumor evolution, the clinical development of FGFRis, the rationale for FGFRi–ICI combinations, current trials, and prospective research directions. Full article
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