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Open AccessEditorial

Editorial for the Special Issue “Latest Review Papers in Molecular Oncology 2023”

by Carmine Stolfi

Int. J. Mol. Sci. 2024, 25(6), 3257; https://doi.org/10.3390/ijms25063257 - 13 Mar 2024

Viewed by 460

Human cancers are products of multistep processes resulting in abnormal cell growth and differentiation, along with a loss of apoptotic function, leading to the uncontrolled expansion of neoplastic cells and their spread to surrounding tissues and, ultimately, distant parts of the body [...] [...] Read more.

Human cancers are products of multistep processes resulting in abnormal cell growth and differentiation, along with a loss of apoptotic function, leading to the uncontrolled expansion of neoplastic cells and their spread to surrounding tissues and, ultimately, distant parts of the body [...] Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

Review

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21 pages, 1633 KiB

Open AccessReview

TRAIL-Sensitizing Effects of Flavonoids in Cancer

by Anderson Luiz-Ferreira, Teresa Pacifico, Álefe Cardoso Cruz, Federica Laudisi, Giovanni Monteleone and Carmine Stolfi

Int. J. Mol. Sci. 2023, 24(23), 16596; https://doi.org/10.3390/ijms242316596 - 22 Nov 2023

Cited by 1 | Viewed by 1016

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without altering the cellular machinery of healthy cells. Unfortunately, the presence of TRAIL resistance mechanisms in a variety of cancer types represents a major [...] Read more.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without altering the cellular machinery of healthy cells. Unfortunately, the presence of TRAIL resistance mechanisms in a variety of cancer types represents a major hurdle, thus limiting the use of TRAIL as a single agent. Accumulating studies have shown that TRAIL-mediated apoptosis can be facilitated in resistant tumors by combined treatment with antitumor agents, ranging from synthetic molecules to natural products. Among the latter, flavonoids, the most prevalent polyphenols in plants, have shown remarkable competence in improving TRAIL-driven apoptosis in resistant cell lines as well as tumor-bearing mice with minimal side effects. Here, we summarize the molecular mechanisms, such as the upregulation of death receptor (DR)4 and DR5 and downregulation of key anti-apoptotic proteins [e.g., cellular FLICE-inhibitory protein (c-FLIP), X-linked inhibitor of apoptosis protein (XIAP), survivin], underlying the TRAIL-sensitizing properties of different classes of flavonoids (e.g., flavones, flavonols, isoflavones, chalcones, prenylflavonoids). Finally, we discuss limitations, mainly related to bioavailability issues, and future perspectives regarding the clinical use of flavonoids as adjuvant agents in TRAIL-based therapies. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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28 pages, 8020 KiB

Open AccessReview

The Price of Human Evolution: Cancer-Testis Antigens, the Decline in Male Fertility and the Increase in Cancer

by Jekaterina Erenpreisa, Ninel Miriam Vainshelbaum, Marija Lazovska, Roberts Karklins, Kristine Salmina, Pawel Zayakin, Felikss Rumnieks, Inna Inashkina, Dace Pjanova and Juris Erenpreiss

Int. J. Mol. Sci. 2023, 24(14), 11660; https://doi.org/10.3390/ijms241411660 - 19 Jul 2023

Cited by 2 | Viewed by 1776

Abstract

The increasing frequency of general and particularly male cancer coupled with the reduction in male fertility seen worldwide motivated us to seek a potential evolutionary link between these two phenomena, concerning the reproductive transcriptional modules observed in cancer and the expression of cancer-testis [...] Read more.

The increasing frequency of general and particularly male cancer coupled with the reduction in male fertility seen worldwide motivated us to seek a potential evolutionary link between these two phenomena, concerning the reproductive transcriptional modules observed in cancer and the expression of cancer-testis antigens (CTA). The phylostratigraphy analysis of the human genome allowed us to link the early evolutionary origin of cancer via the reproductive life cycles of the unicellulars and early multicellulars, potentially driving soma-germ transition, female meiosis, and the parthenogenesis of polyploid giant cancer cells (PGCCs), with the expansion of the CTA multi-families, very late during their evolution. CTA adaptation was aided by retrovirus domestication in the unstable genomes of mammals, for protecting male fertility in stress conditions, particularly that of humans, as compensation for the energy consumption of a large complex brain which also exploited retrotransposition. We found that the early and late evolutionary branches of human cancer are united by the immunity-proto-placental network, which evolved in the Cambrian and shares stress regulators with the finely-tuned sex determination system. We further propose that social stress and endocrine disruption caused by environmental pollution with organic materials, which alter sex determination in male foetuses and further spermatogenesis in adults, bias the development of PGCC-parthenogenetic cancer by default. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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17 pages, 4215 KiB

Open AccessReview

Synchronization between Attractors: Genomic Mechanism of Cell-Fate Change

by Masa Tsuchiya, Paul Brazhnik, Mariano Bizzarri and Alessandro Giuliani

Int. J. Mol. Sci. 2023, 24(14), 11603; https://doi.org/10.3390/ijms241411603 - 18 Jul 2023

Viewed by 1538

Abstract

Herein, we provide a brief overview of complex systems theory approaches to investigate the genomic mechanism of cell-fate changes. Cell trajectories across the epigenetic landscape, whether in development, environmental responses, or disease progression, are controlled by extensively coordinated genome-wide gene expression changes. The [...] Read more.

Herein, we provide a brief overview of complex systems theory approaches to investigate the genomic mechanism of cell-fate changes. Cell trajectories across the epigenetic landscape, whether in development, environmental responses, or disease progression, are controlled by extensively coordinated genome-wide gene expression changes. The elucidation of the mechanisms underlying these coherent expression changes is of fundamental importance in cell biology and for paving the road to new therapeutic approaches. In previous studies, we pointed at dynamic criticality as a plausible characteristic of genome-wide transition dynamics guiding cell fate. Whole-genome expression develops an engine-like organization (genome engine) in order to establish an autonomous dynamical system, capable of both homeostasis and transition behaviors. A critical set of genes behaves as a critical point (CP) that serves as the organizing center of cell-fate change. When the system is pushed away from homeostasis, the state change that occurs at the CP makes local perturbation spread over the genome, demonstrating self-organized critical (SOC) control of genome expression. Oscillating-Mode genes (which normally keep genome expression on pace with microenvironment fluctuations), when in the presence of an effective perturbative stimulus, drive the dynamics of synchronization, and thus guide the cell-fate transition. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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23 pages, 1443 KiB

Open AccessReview

Liposomes in Cancer Therapy: How Did We Start and Where Are We Now

by Melody D. Fulton and Wided Najahi-Missaoui

Int. J. Mol. Sci. 2023, 24(7), 6615; https://doi.org/10.3390/ijms24076615 - 01 Apr 2023

Cited by 31 | Viewed by 4953

Abstract

Since their first discovery in the 1960s by Alec Bangham, liposomes have been shown to be effective drug delivery systems for treating various cancers. Several liposome-based formulations received approval by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), with [...] Read more.

Since their first discovery in the 1960s by Alec Bangham, liposomes have been shown to be effective drug delivery systems for treating various cancers. Several liposome-based formulations received approval by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), with many others in clinical trials. Liposomes have several advantages, including improved pharmacokinetic properties of the encapsulated drug, reduced systemic toxicity, extended circulation time, and targeted disposition in tumor sites due to the enhanced permeability and retention (EPR) mechanism. However, it is worth noting that despite their efficacy in treating various cancers, liposomes still have some potential toxicity and lack specific targeting and disposition. This explains, in part, why their translation into the clinic has progressed only incrementally, which poses the need for more research to focus on addressing such translational limitations. This review summarizes the main properties of liposomes, their current status in cancer therapy, and their limitations and challenges to achieving maximal therapeutic efficacy. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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21 pages, 2103 KiB

Open AccessReview

Autophagy: A Potential Therapeutic Target to Tackle Drug Resistance in Multiple Myeloma

by Hamed Bashiri and Hossein Tabatabaeian

Int. J. Mol. Sci. 2023, 24(7), 6019; https://doi.org/10.3390/ijms24076019 - 23 Mar 2023

Cited by 6 | Viewed by 2501

Abstract

Multiple myeloma (MM) is the second most prevalent hematologic malignancy. In the past few years, the survival of MM patients has increased due to the emergence of novel drugs and combination therapies. Nevertheless, one of the significant obstacles in treating most MM patients [...] Read more.

Multiple myeloma (MM) is the second most prevalent hematologic malignancy. In the past few years, the survival of MM patients has increased due to the emergence of novel drugs and combination therapies. Nevertheless, one of the significant obstacles in treating most MM patients is drug resistance, especially for individuals who have experienced relapses or developed resistance to such cutting-edge treatments. One of the critical processes in developing drug resistance in MM is autophagic activity, an intracellular self-digestive process. Several possible strategies of autophagy involvement in the induction of MM-drug resistance have been demonstrated thus far. In multiple myeloma, it has been shown that High mobility group box protein 1 (HMGB1)-dependent autophagy can contribute to drug resistance. Moreover, activation of autophagy via proteasome suppression induces drug resistance. Additionally, the effectiveness of clarithromycin as a supplemental drug in treating MM has been reported recently, in which autophagy blockage is proposed as one of the potential action mechanisms of CAM. Thus, a promising therapeutic approach that targets autophagy to trigger the death of MM cells and improve drug susceptibility could be considered. In this review, autophagy has been addressed as a survival strategy crucial for drug resistance in MM. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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39 pages, 2543 KiB

Open AccessReview

Chalcones and Gastrointestinal Cancers: Experimental Evidence

by Radka Michalkova, Martin Kello, Martina Cizmarikova, Annamaria Bardelcikova, Ladislav Mirossay and Jan Mojzis

Int. J. Mol. Sci. 2023, 24(6), 5964; https://doi.org/10.3390/ijms24065964 - 22 Mar 2023

Cited by 11 | Viewed by 2931

Abstract

Colorectal (CRC) and gastric cancers (GC) are the most common digestive tract cancers with a high incidence rate worldwide. The current treatment including surgery, chemotherapy or radiotherapy has several limitations such as drug toxicity, cancer recurrence or drug resistance and thus it is [...] Read more.

Colorectal (CRC) and gastric cancers (GC) are the most common digestive tract cancers with a high incidence rate worldwide. The current treatment including surgery, chemotherapy or radiotherapy has several limitations such as drug toxicity, cancer recurrence or drug resistance and thus it is a great challenge to discover an effective and safe therapy for CRC and GC. In the last decade, numerous phytochemicals and their synthetic analogs have attracted attention due to their anticancer effect and low organ toxicity. Chalcones, plant-derived polyphenols, received marked attention due to their biological activities as well as for relatively easy structural manipulation and synthesis of new chalcone derivatives. In this study, we discuss the mechanisms by which chalcones in both in vitro and in vivo conditions suppress cancer cell proliferation or cancer formation. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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15 pages, 668 KiB

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The Gut Microbiome, Microsatellite Status and the Response to Immunotherapy in Colorectal Cancer

by Toritseju O. Sillo, Andrew D. Beggs, Gary Middleton and Akinfemi Akingboye

Int. J. Mol. Sci. 2023, 24(6), 5767; https://doi.org/10.3390/ijms24065767 - 17 Mar 2023

Cited by 3 | Viewed by 2415

Abstract

There is increasing evidence in a range of cancer types that the microbiome plays a direct role in modulating the anti-cancer immune response both at the gut level and systemically. Differences in the gut microbiota have been shown to correlate with differences in [...] Read more.

There is increasing evidence in a range of cancer types that the microbiome plays a direct role in modulating the anti-cancer immune response both at the gut level and systemically. Differences in the gut microbiota have been shown to correlate with differences in immunotherapy responses in a range of non-gastrointestinal tract cancers. DNA mismatch repair-deficient (dMMR) colorectal cancer (CRC) is radically different to DNA mismatch repair-proficient (pMMR) CRC in clinical phenotype and in its very good responses to immunotherapy. While this has usually been thought to be due to the high mutational burden in dMMR CRC, the gut microbiome is radically different in dMMR and pMMR CRC in terms of both composition and diversity. It is probable that differences in the gut microbiota contribute to the varied responses to immunotherapy in dMMR versus pMMR CRC. Targeting the microbiome offers a way to boost the response and increase the selection of patients who might benefit from this therapy. This paper reviews the available literature on the role of the microbiome in the response to immunotherapy in dMMR and pMMR CRC, explores the potential causal relationship and discusses future directions for study in this exciting and rapidly changing field. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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26 pages, 1944 KiB

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Regulation of Cell Plasticity by Bromodomain and Extraterminal Domain (BET) Proteins: A New Perspective in Glioblastoma Therapy

by Deborah Gargano, Marco Segatto and Sabrina Di Bartolomeo

Int. J. Mol. Sci. 2023, 24(6), 5665; https://doi.org/10.3390/ijms24065665 - 16 Mar 2023

Cited by 2 | Viewed by 2041

Abstract

BET proteins are a family of multifunctional epigenetic readers, mainly involved in transcriptional regulation through chromatin modelling. Transcriptome handling ability of BET proteins suggests a key role in the modulation of cell plasticity, both in fate decision and in lineage commitment during embryonic [...] Read more.

BET proteins are a family of multifunctional epigenetic readers, mainly involved in transcriptional regulation through chromatin modelling. Transcriptome handling ability of BET proteins suggests a key role in the modulation of cell plasticity, both in fate decision and in lineage commitment during embryonic development and in pathogenic conditions, including cancerogenesis. Glioblastoma is the most aggressive form of glioma, characterized by a very poor prognosis despite the application of a multimodal therapy. Recently, new insights are emerging about the glioblastoma cellular origin, leading to the hypothesis that several putative mechanisms occur during gliomagenesis. Interestingly, epigenome dysregulation associated with loss of cellular identity and functions are emerging as crucial features of glioblastoma pathogenesis. Therefore, the emerging roles of BET protein in glioblastoma onco-biology and the compelling demand for more effective therapeutic strategies suggest that BET family members could be promising targets for translational breakthroughs in glioblastoma treatment. Primarily, “Reprogramming Therapy”, which is aimed at reverting the malignant phenotype, is now considered a promising strategy for GBM therapy. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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23 pages, 1115 KiB

Open AccessReview

Dialog beyond the Grave: Necrosis in the Tumor Microenvironment and Its Contribution to Tumor Growth

by Emilija Zapletal, Tea Vasiljevic, Pierre Busson and Tanja Matijevic Glavan

Int. J. Mol. Sci. 2023, 24(6), 5278; https://doi.org/10.3390/ijms24065278 - 09 Mar 2023

Cited by 4 | Viewed by 2286

Abstract

Damage-associated molecular patterns (DAMPs) are endogenous molecules released from the necrotic cells dying after exposure to various stressors. After binding to their receptors, they can stimulate various signaling pathways in target cells. DAMPs are especially abundant in the microenvironment of malignant tumors and [...] Read more.

Damage-associated molecular patterns (DAMPs) are endogenous molecules released from the necrotic cells dying after exposure to various stressors. After binding to their receptors, they can stimulate various signaling pathways in target cells. DAMPs are especially abundant in the microenvironment of malignant tumors and are suspected to influence the behavior of malignant and stromal cells in multiple ways often resulting in promotion of cell proliferation, migration, invasion, and metastasis, as well as increased immune evasion. This review will start with a reminder of the main features of cell necrosis, which will be compared to other forms of cell death. Then we will summarize the various methods used to assess tumor necrosis in clinical practice including medical imaging, histopathological examination, and/or biological assays. We will also consider the importance of necrosis as a prognostic factor. Then the focus will be on the DAMPs and their role in the tumor microenvironment (TME). We will address not only their interactions with the malignant cells, frequently leading to cancer progression, but also with the immune cells and their contribution to immunosuppression. Finally, we will emphasize the role of DAMPs released by necrotic cells in the activation of Toll-like receptors (TLRs) and the possible contributions of TLRs to tumor development. This last point is very important for the future of cancer therapeutics since there are attempts to use TLR artificial ligands for cancer therapeutics. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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17 pages, 837 KiB

Open AccessReview

Impacts of Environmental Pollution on Brain Tumorigenesis

by Cristina Pagano, Giovanna Navarra, Laura Coppola, Beatrice Savarese, Giorgio Avilia, Antonella Giarra, Giovanni Pagano, Alessandra Marano, Marco Trifuoggi, Maurizio Bifulco and Chiara Laezza

Int. J. Mol. Sci. 2023, 24(5), 5045; https://doi.org/10.3390/ijms24055045 - 06 Mar 2023

Cited by 4 | Viewed by 4053

Abstract

Pollutants consist of several components, known as direct or indirect mutagens, that can be associated with the risk of tumorigenesis. The increased incidence of brain tumors, observed more frequently in industrialized countries, has generated a deeper interest in examining different pollutants that could [...] Read more.

Pollutants consist of several components, known as direct or indirect mutagens, that can be associated with the risk of tumorigenesis. The increased incidence of brain tumors, observed more frequently in industrialized countries, has generated a deeper interest in examining different pollutants that could be found in food, air, or water supply. These compounds, due to their chemical nature, alter the activity of biological molecules naturally found in the body. The bioaccumulation leads to harmful effects for humans, increasing the risk of the onset of several pathologies, including cancer. Environmental components often combine with other risk factors, such as the individual genetic component, which increases the chance of developing cancer. The objective of this review is to discuss the impact of environmental carcinogens on modulating the risk of brain tumorigenesis, focusing our attention on certain categories of pollutants and their sources. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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26 pages, 3214 KiB

Open AccessReview

Endoplasmic Reticulum Stress in Renal Cell Carcinoma

by Marta Correia de Sousa, Etienne Delangre, Miranda Türkal, Michelangelo Foti and Monika Gjorgjieva

Int. J. Mol. Sci. 2023, 24(5), 4914; https://doi.org/10.3390/ijms24054914 - 03 Mar 2023

Cited by 4 | Viewed by 2749

Abstract

The endoplasmic reticulum is an organelle exerting crucial functions in protein production, metabolism homeostasis and cell signaling. Endoplasmic reticulum stress occurs when cells are damaged and the capacity of this organelle to perform its normal functions is reduced. Subsequently, specific signaling cascades, together [...] Read more.

The endoplasmic reticulum is an organelle exerting crucial functions in protein production, metabolism homeostasis and cell signaling. Endoplasmic reticulum stress occurs when cells are damaged and the capacity of this organelle to perform its normal functions is reduced. Subsequently, specific signaling cascades, together forming the so-called unfolded protein response, are activated and deeply impact cell fate. In normal renal cells, these molecular pathways strive to either resolve cell injury or activate cell death, depending on the extent of cell damage. Therefore, the activation of the endoplasmic reticulum stress pathway was suggested as an interesting therapeutic strategy for pathologies such as cancer. However, renal cancer cells are known to hijack these stress mechanisms and exploit them to their advantage in order to promote their survival through rewiring of their metabolism, activation of oxidative stress responses, autophagy, inhibition of apoptosis and senescence. Recent data strongly suggest that a certain threshold of endoplasmic reticulum stress activation needs to be attained in cancer cells in order to shift endoplasmic reticulum stress responses from a pro-survival to a pro-apoptotic outcome. Several endoplasmic reticulum stress pharmacological modulators of interest for therapeutic purposes are already available, but only a handful were tested in the case of renal carcinoma, and their effects in an in vivo setting remain poorly known. This review discusses the relevance of endoplasmic reticulum stress activation or suppression in renal cancer cell progression and the therapeutic potential of targeting this cellular process for this cancer. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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14 pages, 959 KiB

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The Role of NLRP3, a Star of Excellence in Myeloproliferative Neoplasms

by Elisa Parciante, Cosimo Cumbo, Luisa Anelli, Antonella Zagaria, Immacolata Redavid, Angela Minervini, Maria Rosa Conserva, Giuseppina Tota, Nicoletta Coccaro, Francesco Tarantini, Crescenzio Francesco Minervini, Maria Giovanna Macchia, Giorgina Specchia, Pellegrino Musto and Francesco Albano

Int. J. Mol. Sci. 2023, 24(5), 4860; https://doi.org/10.3390/ijms24054860 - 02 Mar 2023

Cited by 1 | Viewed by 1719

Abstract

Nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) is the most widely investigated inflammasome member whose overactivation can be a driver of several carcinomas. It is activated in response to different signals and plays an important role in metabolic disorders and inflammatory and autoimmune [...] Read more.

Nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) is the most widely investigated inflammasome member whose overactivation can be a driver of several carcinomas. It is activated in response to different signals and plays an important role in metabolic disorders and inflammatory and autoimmune diseases. NLRP3 belongs to the pattern recognition receptors (PRRs) family, expressed in numerous immune cells, and it plays its primary function in myeloid cells. NLRP3 has a crucial role in myeloproliferative neoplasms (MPNs), considered to be the diseases best studied in the inflammasome context. The investigation of the NLRP3 inflammasome complex is a new horizon to explore, and inhibiting IL-1β or NLRP3 could be a helpful cancer-related therapeutic strategy to improve the existing protocols. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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17 pages, 967 KiB

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The Role of BCL-2 and PD-1/PD-L1 Pathway in Pathogenesis of Myelodysplastic Syndromes

by Bartłomiej Kuszczak, Tomasz Wróbel, Katarzyna Wicherska-Pawłowska and Justyna Rybka

Int. J. Mol. Sci. 2023, 24(5), 4708; https://doi.org/10.3390/ijms24054708 - 01 Mar 2023

Cited by 2 | Viewed by 2637

Abstract

Myelodysplastic syndromes (MDSs) belong to a group of clonal bone marrow malignancies. In light of the emergence of new molecules, a significant contribution to the understanding of the pathogenesis of the disease is the study of the B-cell CLL/lymphoma 2 (BCL-2) and the [...] Read more.

Myelodysplastic syndromes (MDSs) belong to a group of clonal bone marrow malignancies. In light of the emergence of new molecules, a significant contribution to the understanding of the pathogenesis of the disease is the study of the B-cell CLL/lymphoma 2 (BCL-2) and the programmed cell death receptor 1 (PD-1) protein and its ligands. BCL-2-family proteins are involved in the regulation of the intrinsic apoptosis pathway. Disruptions in their interactions promote the progression and resistance of MDSs. They have become an important target for specific drugs. Bone marrow cytoarchitecture may prove to be a predictor of response to its use. The challenge is the observed resistance to venetoclax, for which the MCL-1 protein may be largely responsible. Molecules with the potential to break the associated resistance include S63845, S64315, chidamide and arsenic trioxide (ATO). Despite promising in vitro studies, the role of PD-1/PD-L1 pathway inhibitors has not yet been established. Knockdown of the PD-L1 gene in preclinical studies was associated with increased levels of BCL-2 and MCL-1 in lymphocytes T, which could increase their survival and promote tumor apoptosis. A trial (NCT03969446) is currently underway to combine inhibitors from both groups. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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25 pages, 740 KiB

Open AccessReview

Radiogenomics in Renal Cancer Management—Current Evidence and Future Prospects

by Matteo Ferro, Gennaro Musi, Michele Marchioni, Martina Maggi, Alessandro Veccia, Francesco Del Giudice, Biagio Barone, Felice Crocetto, Francesco Lasorsa, Alessandro Antonelli, Luigi Schips, Riccardo Autorino, Gian Maria Busetto, Daniela Terracciano, Giuseppe Lucarelli and Octavian Sabin Tataru

Int. J. Mol. Sci. 2023, 24(5), 4615; https://doi.org/10.3390/ijms24054615 - 27 Feb 2023

Cited by 34 | Viewed by 3355

Abstract

Renal cancer management is challenging from diagnosis to treatment and follow-up. In cases of small renal masses and cystic lesions the differential diagnosis of benign or malignant tissues has potential pitfalls when imaging or even renal biopsy is applied. The recent artificial intelligence, [...] Read more.

Renal cancer management is challenging from diagnosis to treatment and follow-up. In cases of small renal masses and cystic lesions the differential diagnosis of benign or malignant tissues has potential pitfalls when imaging or even renal biopsy is applied. The recent artificial intelligence, imaging techniques, and genomics advancements have the ability to help clinicians set the stratification risk, treatment selection, follow-up strategy, and prognosis of the disease. The combination of radiomics features and genomics data has achieved good results but is currently limited by the retrospective design and the small number of patients included in clinical trials. The road ahead for radiogenomics is open to new, well-designed prospective studies, with large cohorts of patients required to validate previously obtained results and enter clinical practice. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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40 pages, 2229 KiB

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Crosstalk of Inflammatory Cytokines within the Breast Tumor Microenvironment

by Ola Habanjar, Rea Bingula, Caroline Decombat, Mona Diab-Assaf, Florence Caldefie-Chezet and Laetitia Delort

Int. J. Mol. Sci. 2023, 24(4), 4002; https://doi.org/10.3390/ijms24044002 - 16 Feb 2023

Cited by 30 | Viewed by 5962

Abstract

Several immune and immunocompetent cells, including dendritic cells, macrophages, adipocytes, natural killer cells, T cells, and B cells, are significantly correlated with the complex discipline of oncology. Cytotoxic innate and adaptive immune cells can block tumor proliferation, and others can prevent the immune [...] Read more.

Several immune and immunocompetent cells, including dendritic cells, macrophages, adipocytes, natural killer cells, T cells, and B cells, are significantly correlated with the complex discipline of oncology. Cytotoxic innate and adaptive immune cells can block tumor proliferation, and others can prevent the immune system from rejecting malignant cells and provide a favorable environment for tumor progression. These cells communicate with the microenvironment through cytokines, a chemical messenger, in an endocrine, paracrine, or autocrine manner. These cytokines play an important role in health and disease, particularly in host immune responses to infection and inflammation. They include chemokines, interleukins (ILs), adipokines, interferons, colony-stimulating factors (CSFs), and tumor necrosis factor (TNF), which are produced by a wide range of cells, including immune cells, such as macrophages, B-cells, T-cells, and mast cells, as well as endothelial cells, fibroblasts, a variety of stromal cells, and some cancer cells. Cytokines play a crucial role in cancer and cancer-related inflammation, with direct and indirect effects on tumor antagonistic or tumor promoting functions. They have been extensively researched as immunostimulatory mediators to promote the generation, migration and recruitment of immune cells that contribute to an effective antitumor immune response or pro-tumor microenvironment. Thus, in many cancers such as breast cancer, cytokines including leptin, IL-1B, IL-6, IL-8, IL-23, IL-17, and IL-10 stimulate while others including IL-2, IL-12, and IFN-γ, inhibit cancer proliferation and/or invasion and enhance the body’s anti-tumor defense. Indeed, the multifactorial functions of cytokines in tumorigenesis will advance our understanding of cytokine crosstalk pathways in the tumor microenvironment, such as JAK/STAT, PI3K, AKT, Rac, MAPK, NF-κB, JunB, cFos, and mTOR, which are involved in angiogenesis, cancer proliferation and metastasis. Accordingly, targeting and blocking tumor-promoting cytokines or activating and amplifying tumor-inhibiting cytokines are considered cancer-directed therapies. Here, we focus on the role of the inflammatory cytokine system in pro- and anti-tumor immune responses, discuss cytokine pathways involved in immune responses to cancer and some anti-cancer therapeutic applications. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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32 pages, 1004 KiB

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The Roles of Epigenetic Regulation and the Tumor Microenvironment in the Mechanism of Resistance to Systemic Therapy in Hepatocellular Carcinoma

by Kyoko Oura, Asahiro Morishita, Sae Hamaya, Koji Fujita and Tsutomu Masaki

Int. J. Mol. Sci. 2023, 24(3), 2805; https://doi.org/10.3390/ijms24032805 - 01 Feb 2023

Cited by 7 | Viewed by 3434

Abstract

Primary liver cancer is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a major histologic type with a poor prognosis owing to the difficulty in early detection, the chemotherapy resistance, and the [...] Read more.

Primary liver cancer is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a major histologic type with a poor prognosis owing to the difficulty in early detection, the chemotherapy resistance, and the high recurrence rate of the disease. Despite recent advancements in HCC prevention and diagnosis, over 50% of patients are diagnosed at Barcelona Clinic Liver Cancer Stage B or C. Systemic therapies are recommended for unresectable HCC (uHCC) with major vascular invasion, extrahepatic metastases, or intrahepatic lesions that have a limited response to transcatheter arterial chemoembolization, but the treatment outcome tends to be unsatisfactory due to acquired drug resistance. Elucidation of the mechanisms underlying the resistance to systemic therapies and the appropriate response strategies to solve this issue will contribute to improved outcomes in the multidisciplinary treatment of uHCC. In this review, we summarize recent findings on the mechanisms of resistance to drugs such as sorafenib, regorafenib, and lenvatinib in molecularly targeted therapy, with a focus on epigenetic regulation and the tumor microenvironment and outline the approaches to improve the therapeutic outcome for patients with advanced HCC. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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27 pages, 2178 KiB

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From the Catastrophic Objective Irreproducibility of Cancer Research and Unavoidable Failures of Molecular Targeted Therapies to the Sparkling Hope of Supramolecular Targeted Strategies

by Irina Alekseenko, Liya Kondratyeva, Igor Chernov and Eugene Sverdlov

Int. J. Mol. Sci. 2023, 24(3), 2796; https://doi.org/10.3390/ijms24032796 - 01 Feb 2023

Cited by 2 | Viewed by 2307

Abstract

The unprecedented non-reproducibility of the results published in the field of cancer research has recently come under the spotlight. In this short review, we try to highlight some general principles in the organization and evolution of cancerous tumors, which objectively lead to their [...] Read more.

The unprecedented non-reproducibility of the results published in the field of cancer research has recently come under the spotlight. In this short review, we try to highlight some general principles in the organization and evolution of cancerous tumors, which objectively lead to their enormous variability and, consequently, the irreproducibility of the results of their investigation. This heterogeneity is also extremely unfavorable for the effective use of molecularly targeted medicine. Against the seemingly comprehensive background of this heterogeneity, we single out two supramolecular characteristics common to all tumors: the clustered nature of tumor interactions with their microenvironment and the formation of biomolecular condensates with tumor-specific distinctive features. We suggest that these features can form the basis of strategies for tumor-specific supramolecular targeted therapies. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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Open AccessReview

Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors

by Ester Blanco, Luisa Chocarro, Leticia Fernández-Rubio, Ana Bocanegra, Hugo Arasanz, Miriam Echaide, Maider Garnica, Sergio Piñeiro-Hermida, Grazyna Kochan and David Escors

Int. J. Mol. Sci. 2023, 24(3), 2676; https://doi.org/10.3390/ijms24032676 - 31 Jan 2023

Cited by 6 | Viewed by 2760

Abstract

Immunotherapies based on immune checkpoint blockade have shown remarkable clinical outcomes and durable responses in patients with many tumor types. Nevertheless, these therapies lack efficacy in most cancer patients, even causing severe adverse events in a small subset of patients, such as inflammatory [...] Read more.

Immunotherapies based on immune checkpoint blockade have shown remarkable clinical outcomes and durable responses in patients with many tumor types. Nevertheless, these therapies lack efficacy in most cancer patients, even causing severe adverse events in a small subset of patients, such as inflammatory disorders and hyper-progressive disease. To diminish the risk of developing serious toxicities, intratumor delivery of monoclonal antibodies could be a solution. Encouraging results have been shown in both preclinical and clinical studies. Thus, intratumor immunotherapy as a new strategy may retain efficacy while increasing safety. This approach is still an exploratory frontier in cancer research and opens up new possibilities for next-generation personalized medicine. Local intratumor delivery can be achieved through many means, but an attractive approach is the use of gene therapy vectors expressing mAbs inside the tumor mass. Here, we summarize basic, translational, and clinical results of intratumor mAb delivery, together with descriptions of non-viral and viral strategies for mAb delivery in preclinical and clinical development. Currently, this is an expanding research subject that will surely play a key role in the future of oncology. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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21 pages, 3296 KiB

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Comparative Efficacy of ALK Inhibitors for Treatment-Naïve ALK-Positive Advanced Non-Small Cell Lung Cancer with Central Nervous System Metastasis: A Network Meta-Analysis

by Koichi Ando, Ryo Manabe, Yasunari Kishino, Sojiro Kusumoto, Toshimitsu Yamaoka, Akihiko Tanaka, Tohru Ohmori and Hironori Sagara

Int. J. Mol. Sci. 2023, 24(3), 2242; https://doi.org/10.3390/ijms24032242 - 23 Jan 2023

Cited by 6 | Viewed by 4615

Abstract

Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC). Thus, this review aimed to provide a comprehensive overview of brain metastasis, acquired resistance, and prospects for overcoming these [...] Read more.

Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC). Thus, this review aimed to provide a comprehensive overview of brain metastasis, acquired resistance, and prospects for overcoming these challenges. A network meta-analysis of relevant phase III randomized controlled trials was performed to compare the efficacies of multiple ALK inhibitors by drug and generation in overall patients with ALK-p untreated advanced NSCLC and a subgroup of patients with CNS metastases. The primary endpoint was progression-free survival (PFS). Generation-specific comparison results showed that third-generation ALK inhibitors were significantly more effective than second-generation ALK inhibitors in prolonging the PFS of the subgroup of patients with CNS metastases. Drug-specific comparison results demonstrated that lorlatinib was the most effective in prolonging PFS, followed by brigatinib, alectinib, ensartinib, ceritinib, crizotinib, and chemotherapy. While lorlatinib was superior to brigatinib for PFS in the overall patient population, no significant difference between the two was found in the subgroup of patients with CNS metastases. These results can serve as a foundation for basic, clinical, and translational research and guide clinical oncologists in developing individualized treatment strategies for patients with ALK-p, ALK inhibitor-naive advanced NSCLC. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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