Roles of TGF-ß signals in tumor microenvironment via regulation of the formation and plasticity of vascular system.

Tumor cells evolve in tumor microenvironment composed of multiple cell types. Among these, endothelial cells (ECs) are the major players in tumor angiogenesis, which is a driver of tumor progression and metastasis. Increasing evidence suggests that ECs also contribute to tumor progression and metastasis as they modify their phenotypes to differentiate into mesenchymal cells through a process known as endothelial-mesenchymal transition (EndoMT). This plasticity of ECs is mediated by various cytokines, including transforming growth factor-ß (TGF-ß), and modulated by other stimuli depending on the cellular contexts. Recent lines of evidence have shown that EndoMT is involved in various steps of tumor progression, including tumor angiogenesis, intravasation and extravasation of cancer cells, formation of cancer-associated fibroblasts, and cancer therapy resistance. In this review, we summarize current updates on EndoMT, highlight the roles of EndoMT in tumor progression and metastasis, and underline targeting EndoMT as a potential therapeutic strategy.

Tricarboxylic Acid Cycle Relationships with Non-Metabolic Processes: A Short Story with DNA Repair and Its Consequences on Cancer Therapy Resistance.

Metabolic changes involving the tricarboxylic acid (TCA) cycle have been linked to different non-metabolic cell processes. Among them, apart from cancer and immunity, emerges the DNA damage response (DDR) and specifically DNA damage repair. The oncometabolites succinate, fumarate and 2-hydroxyglutarate (2HG) increase reactive oxygen species levels and create pseudohypoxia conditions that induce DNA damage and/or inhibit DNA repair. Additionally, by influencing DDR modulation, they establish direct relationships with DNA repair on at least four different pathways. The AlkB pathway deals with the removal of N-alkylation DNA and RNA damage that is inhibited by fumarate and 2HG. The MGMT pathway acts in the removal of O-alkylation DNA damage, and it is inhibited by the silencing of the MGMT gene promoter by 2HG and succinate. The other two pathways deal with the repair of double-strand breaks (DSBs) but with opposite effects: the FH pathway, which uses fumarate to help with the repair of this damage, and the chromatin remodeling pathway, in which oncometabolites inhibit its repair by impairing the homologous recombination repair (HRR) system. Since oncometabolites inhibit DNA repair, their removal from tumor cells will not always generate a positive response in cancer therapy. In fact, their presence contributes to longer survival and/or sensitization against tumor therapy in some cancer patients.

Introduction of long non-coding RNAs to regulate autophagy-associated therapy resistance in cancer.

Autophagy is a lysosomal degradation pathway that depends on various evolutionarily conserved autophagy-related genes (ATGs). Dysregulation of autophagy plays an important role in the occurrence and development of cancer. Chemotherapy, targeted therapy, radiotherapy, and immunotherapy are important treatment options for cancer, which can significantly improve the survival rate of cancer patients. However, the occurrence of therapy resistance results in therapeutic failure and poor prognosis of cancer. Accumulating studies have found that long non-coding RNAs (lncRNAs) are well known as crucial regulators to control autophagy through regulating ATGs and autophagy-associated signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, ultimately mediating chemoresistance and radioresistance. Taken together, this review systematically summarizes and elucidates the pivotal role of lncRNAs in cancer chemoresistance and radioresistance via regulating autophagy. Understanding the specific mechanism of which may provide autophagy-related therapeutic targets for cancer in the future.

Long non-coding RNAs in drug resistance across the top five cancers: Update on their roles and mechanisms.

Cancer drug resistance stands as a formidable obstacle in the relentless fight against the top five prevalent cancers: breast, lung, colorectal, prostate, and gastric cancers. These malignancies collectively account for a significant portion of cancer-related deaths worldwide. In recent years, long non-coding RNAs (lncRNAs) have emerged as pivotal players in the intricate landscape of cancer biology, and their roles in driving drug resistance are steadily coming to light. This comprehensive review seeks to underscore the paramount significance of lncRNAs in orchestrating resistance across a spectrum of different cancer drugs, including platinum drugs (DDP), tamoxifen, trastuzumab, 5-fluorouracil (5-FU), paclitaxel (PTX), and Androgen Deprivation Therapy (ADT) across the most prevalent types of cancer. It delves into the multifaceted mechanisms through which lncRNAs exert their influence on drug resistance, shedding light on their regulatory roles in various facets of cancer biology. A comprehensive understanding of these lncRNA-mediated mechanisms may pave the way for more effective and personalized treatment strategies, ultimately improving patient outcomes in these challenging malignancies.

The Role of Neutrophil Extracellular Traps in the Outcome of Malignant Epitheliomas: Significance of CA215 Involvement.

Neutrophil extracellular traps (NETs) were originally discovered as a part of the innate immune response of the host to bacteria. They form a web-like structure that can immobilize microorganisms or exhibit direct antimicrobial properties, such as releasing reactive oxygen species (ROS). NETs are established when neutrophils undergo a sort of cellular death following exposure to ROS, chemokines, cytokines, or other soluble factors. This process results in the release of the neutrophil's DNA in a web-like form, which is decorated with citrullinated histones (H3/H4-cit), neutrophil elastase (NE), and myeloperoxidase (MPO). Emerging studies have put into perspective that NETs play an important role in oncology as they were shown to influence tumor growth, malignant initiation, and proliferation, mediate the transition from endothelial to mesenchymal tissue, stimulate angiogenesis or metastasis, and can even help cancer cells evade the immune response. The role of NETs in cancer therapy resides in their ability to form and act as a mechanical barrier that will provide the primary tumor with a reduced response to irradiation or pharmaceutical penetration. Subsequently, cancer cells are shown to internalize NETs and use them as a strong antioxidant when pharmaceutical treatment is administered. In this review, we explored the role of NETs as part of the tumor microenvironment (TME), in the context of malignant epitheliomas, which are capable of an autonomous production of CA215, a subvariant of IgG, and part of the carcinoembryonic antigen (CEA) superfamily. Studies have shown that CA215 has a functional Fc subdivision able to activate the Fc-gamma-RS receptor on the surface of neutrophils. This activation may afterward stimulate the production of NETs, thus indicating CA215 as a potential factor in cancer therapy surveillance.

The Cancer Antioxidant Regulation System in Therapeutic Resistance.

Antioxidants play a pivotal role in neutralizing reactive oxygen species (ROS), which are known to induce oxidative stress. In the context of cancer development, cancer cells adeptly maintain elevated levels of both ROS and antioxidants through a process termed "redox reprogramming". This balance optimizes the proliferative influence of ROS while simultaneously reducing the potential for ROS to cause damage to the cell. In some cases, the adapted antioxidant machinery can hamper the efficacy of treatments for neoplastic diseases, representing a significant facet of the resistance mechanisms observed in cancer therapy. In this review, we outline the contribution of antioxidant systems to therapeutic resistance. We detail the fundamental constituents of these systems, encompassing the central regulatory mechanisms involving transcription factors (of particular importance is the KEAP1/NRF2 signaling axis), the molecular effectors of antioxidants, and the auxiliary systems responsible for NADPH generation. Furthermore, we present recent clinical trials based on targeted antioxidant systems for the treatment of cancer, assessing the potential as well as challenges of this strategy in cancer therapy. Additionally, we summarize the pressing issues in the field, with the aim of illuminating a path toward the emergence of novel anticancer therapeutic approaches by orchestrating redox signaling.

The multifaceted role of MUC1 in tumor therapy resistance.

Tumor therapeutic resistances are frequently linked to the recurrence and poor prognosis of cancers and have been a key bottleneck in clinical tumor treatment. Mucin1 (MUC1), a heterodimeric transmembrane glycoprotein, exhibits abnormally overexpression in a variety of human tumors and has been confirmed to be related to the formation of therapeutic resistance. In this review, the multifaceted roles of MUC1 in tumor therapy resistance are summarized from aspects of pan-cancer principles shared among therapies and individual mechanisms dependent on different therapies. Concretely, the common mechanisms of therapy resistance across cancers include interfering with gene expression, promoting genome instability, modifying tumor microenvironment, enhancing cancer heterogeneity and stemness, and activating evasion and metastasis. Moreover, the individual mechanisms of therapy resistance in chemotherapy, radiotherapy, and biotherapy are introduced. Last but not least, MUC1-involved therapy resistance in different types of cancers and MUC1-related clinical trials are summarized.

Nuclear morphology predicts cell survival to cisplatin chemotherapy.

The emergence of chemotherapy resistance drives cancer lethality in cancer patients, with treatment initially reducing overall tumor burden followed by resistant recurrent disease. While molecular mechanisms underlying resistance phenotypes have been explored, less is known about the cell biological characteristics of cancer cells that survive to eventually seed the recurrence. To identify the unique phenotypic characteristics associated with survival upon chemotherapy exposure, we characterized nuclear morphology and function as prostate cancer cells recovered following cisplatin treatment. Cells that survived in the days and weeks after treatment and resisted therapy-induced cell death showed increasing cell size and nuclear size, enabled by continuous endocycling resulting in repeated whole genome doubling. We further found that cells that survive after therapy release were predominantly mononucleated and likely employ more efficient DNA damage repair. Finally, we show that surviving cancer cells exhibit a distinct nucleolar phenotype and increased rRNA levels. These data support a paradigm where soon after therapy release, the treated population mostly contains cells with a high level of widespread and catastrophic DNA damage that leads to apoptosis, while the minority of cells that have successful DDR are more likely to access a pro-survival state. These findings are consistent with accession of the polyaneuploid cancer cell (PACC) state, a recently described mechanism of therapy resistance and tumor recurrence. Our findings demonstrate the fate of cancer cells following cisplatin treatment and define key cell phenotypic characteristics of the PACC state. This work is essential for understanding and, ultimately, targeting cancer resistance and recurrence.

Dual-specificity phosphatases: therapeutic targets in cancer therapy resistance.

PURPOSE: Therapy resistance is the principal obstacle to achieving cures in cancer patients and its successful tackling requires a deep understanding of the resistance mediators. Increasing evidence indicates that tumor phosphatases are novel and druggable targets in translational oncology and their modulation may hinder tumor growth and motility and potentiate therapeutic sensitivity in various neoplasms via regulation of various signal transduction pathways. Dual-specificity phosphatases (DUSPs) are key players of cell growth, survival and death and have essential roles in tumor initiation, malignant progression and therapy resistance through regulation of the MAPK signaling pathway. In this review, different aspects of DUSPs are discussed. METHODS: A comprehensive literature review was performed using various websites including PubMed. RESULTS: We provide mechanistic insights into the roles of well-known DUSPs in resistance to a wide range of cancer therapeutic approaches including chemotherapy, radiation and molecular targeted therapy in human malignancies. Moreover, we discuss the development of DUSP modulators, with a focus on DUSP1 and 6 inhibitors. Ultimately, the preclinical investigations of small molecule inhibitors of DUSP1 and 6 are outlined. CONCLUSION: Emerging evidence indicates that the DUSP family is aberrantly expressed in human malignancies and plays critical roles in determining sensitivity to a wide range of cancer therapeutic strategies through regulation of the MAPK signaling pathways. Consequently, targeting DUSPs and their downstream molecules can pave the way for more effective cancer therapies.

Emerging roles of purinergic signaling in anti-cancer therapy resistance.

Cancer is a complex disease with a rapid growing incidence and often characterized by a poor prognosis. Although impressive advances have been made in cancer treatments, resistance to therapy remains a critical obstacle for the improvement of patients outcome. Current treatment approaches as chemo-, radio-, and immuno-therapy deeply affect the tumor microenvironment (TME), inducing an extensive selective pressure on cancer cells through the activation of the immune system, the induction of cell death and the release of inflammatory and damage-associated molecular patterns (DAMPS), including nucleosides (adenosine) and nucleotides (ATP and ADP). To survive in this hostile environment, resistant cells engage a variety of mitigation pathways related to metabolism, DNA repair, stemness, inflammation and resistance to apoptosis. In this context, purinergic signaling exerts a pivotal role being involved in mitochondrial function, stemness, inflammation and cancer development. The activity of ATP and adenosine released in the TME depend upon the repertoire of purinergic P2 and adenosine receptors engaged, as well as, by the expression of ectonucleotidases (CD39 and CD73) on tumor, immune and stromal cells. Besides its well established role in the pathogenesis of several tumors and in host-tumor interaction, purinergic signaling has been recently shown to be profoundly involved in the development of therapy resistance. In this review we summarize the current advances on the role of purinergic signaling in response and resistance to anti-cancer therapies, also describing the translational applications of combining conventional anticancer interventions with therapies targeting purinergic signaling.

Molecular Mechanisms of Anti-Neoplastic and Immune Stimulatory Properties of Oncolytic Newcastle Disease Virus.

Oncolytic viruses represent interesting anti-cancer agents with high tumor selectivity and immune stimulatory potential. The present review provides an update of the molecular mechanisms of the anti-neoplastic and immune stimulatory properties of the avian paramyxovirus, Newcastle Disease Virus (NDV). The anti-neoplastic activities of NDV include (i) the endocytic targeting of the GTPase Rac1 in Ras-transformed human tumorigenic cells; (ii) the switch from cellular protein to viral protein synthesis and the induction of autophagy mediated by viral nucleoprotein NP; (iii) the virus replication mediated by viral RNA polymerase (large protein (L), associated with phosphoprotein (P)); (iv) the facilitation of NDV spread in tumors via the membrane budding of the virus progeny with the help of matrix protein (M) and fusion protein (F); and (v) the oncolysis via apoptosis, necroptosis, pyroptosis, or ferroptosis associated with immunogenic cell death. A special property of this oncolytic virus consists of its potential for breaking therapy resistance in human cancer cells. Eight examples of this important property are presented and explained. In healthy human cells, NDV infection activates the RIG-MAVs immune signaling pathway and establishes an anti-viral state based on a strong and uninhibited interferon α,ß response. The review also describes the molecular determinants and mechanisms of the NDV-mediated immune stimulatory effects, in which the viral hemagglutinin-neuraminidase (HN) protein plays a prominent role. The six viral proteins provide oncolytic NDV with a special profile in the treatment of cancer.

miRNA-based biomarkers, therapies, and resistance in Cancer.

MicroRNAs (miRNAs), small non-coding RNAs (ncRNAs) of about 22 nucleotides in size, play important roles in gene regulation, and their dysregulation is implicated in human diseases including cancer. A variety of miRNAs could take roles in the cancer progression, participate in the process of tumor immune, and function with miRNA sponges. During the last two decades, the connection between miRNAs and various cancers has been widely researched. Based on evidence about miRNA, numerous potential cancer biomarkers for the diagnosis and prognosis have been put forward, providing a new perspective on cancer screening. Besides, there are several miRNA-based therapies among different cancers being conducted, advanced treatments such as the combination of synergistic strategies and the use of complementary miRNAs provide significant clinical benefits to cancer patients potentially. Furthermore, it is demonstrated that many miRNAs are engaged in the resistance of cancer therapies with their complex underlying regulatory mechanisms, whose comprehensive cognition can help clinicians and improve patient prognosis. With the belief that studies about miRNAs in human cancer would have great clinical implications, we attempt to summarize the current situation and potential development prospects in this review.

3D Tissue-Engineered Tumor Model for Ewing's Sarcoma That Incorporates Bone-like ECM and Mineralization.

The tumor microenvironment harbors essential components required for cancer progression including biochemical signals and mechanical cues. To study the effects of microenvironmental elements on Ewing's sarcoma (ES) pathogenesis, we tissue-engineered an acellular three-dimensional (3D) bone tumor niche from electrospun poly(ε-caprolactone) (PCL) scaffolds that incorporate bone-like architecture, extracellular matrix (ECM), and mineralization. PCL-ECM constructs were generated by decellularizing PCL scaffolds harboring cultures of osteogenic human mesenchymal stem cells. The PCL-ECM constructs simulated in vivo-like tumor architecture and increased the proliferation of ES cells compared to PCL scaffolds alone. Compared to monolayer controls, 3D environments facilitated the downregulation of the canonical insulin-like growth factor 1 receptor (IGF-1R) signal cascade through mechanistic target of rapamycin (mTOR), both of which are targets of recent clinical trials. In addition to the downregulation of canonical IGF-1R signaling, 3D environments promoted a reduction in the clathrin-dependent nuclear localization and transcriptional activity of IGF-1R. In vitro drug testing revealed that 3D environments generated cell phenotypes that were resistant to mTOR inhibition and chemotherapy. Our versatile PCL-ECM constructs allow for the investigation of the roles of various microenvironmental elements in ES tumor growth, cancer cell morphology, and induction of resistant cell phenotypes.

YAP/TAZ Signaling and Resistance to Cancer Therapy.

Drug resistance is a major challenge in cancer treatment. Emerging evidence indicates that deregulation of YAP/TAZ signaling may be a major mechanism of intrinsic and acquired resistance to various targeted and chemotherapies. Moreover, YAP/TAZ-mediated expression of PD-L1 and multiple cytokines is pivotal for tumor immune evasion. While direct inhibitors of YAP/TAZ are still under development, FDA-approved drugs that indirectly block YAP/TAZ activation or critical downstream targets of YAP/TAZ have shown promise in the clinic in reducing therapy resistance. Finally, BET inhibitors, which reportedly block YAP/TAZ-mediated transcription, present another potential venue to overcome YAP/TAZ-induced drug resistance.

Mitophagy in Cancer: A Tale of Adaptation.

：In the past years, we have learnt that tumors co-evolve with their microenvironment, and that the active interaction between cancer cells and stromal cells plays a pivotal role in cancer initiation, progression and treatment response. Among the players involved, the pathways regulating mitochondrial functions have been shown to be crucial for both cancer and stromal cells. This is perhaps not surprising, considering that mitochondria in both cancerous and non-cancerous cells are decisive for vital metabolic and bioenergetic functions and to elicit cell death. The central part played by mitochondria also implies the existence of stringent mitochondrial quality control mechanisms, where a specialized autophagy pathway (mitophagy) ensures the selective removal of damaged or dysfunctional mitochondria. Although the molecular underpinnings of mitophagy regulation in mammalian cells remain incomplete, it is becoming clear that mitophagy pathways are intricately linked to the metabolic rewiring of cancer cells to support the high bioenergetic demand of the tumor. In this review, after a brief introduction of the main mitophagy regulators operating in mammalian cells, we discuss emerging cell autonomous roles of mitochondria quality control in cancer onset and progression. We also discuss the relevance of mitophagy in the cellular crosstalk with the tumor microenvironment and in anti-cancer therapy responses.

Mechanoregulation and pathology of YAP/TAZ via Hippo and non-Hippo mechanisms.

Yes-associated protein (YAP) and its paralog WW domain containing transcription regulator 1 (TAZ) are important regulators of multiple cellular functions such as proliferation, differentiation, and survival. On the tissue level, YAP/TAZ are essential for embryonic development, organ size control and regeneration, while their deregulation leads to carcinogenesis or other diseases. As an underlying principle for YAP/TAZ-mediated regulation of biological functions, a growing body of research reveals that YAP/TAZ play a central role in delivering information of mechanical environments surrounding cells to the nucleus transcriptional machinery. In this review, we discuss mechanical cue-dependent regulatory mechanisms for YAP/TAZ functions, as well as their clinical significance in cancer progression and treatment.