Editor’s Choice Articles

Photodynamic therapy (PDT) is a promising therapy against cancer. Even though it has been investigated for more than 100 years, scientific publications have grown exponentially in the last two decades. For this reason, we present a brief compendium of reviews of the last two decades classified under different topics, namely, overviews, reviews about specific cancers, and meta-analyses of photosensitisers, PDT mechanisms, dosimetry, and light sources. The key issues and main conclusions are summarized, including ways and means to improve therapy and outcomes. Due to the broad scope of this work and it being the first time that a compendium of the latest reviews has been performed for PDT, it may be of interest to a wide audience. Full article

Melanoma is reported as the 19th most common cancer worldwide, with estimated age-standardized incidence rates of 2.8–3.1 per 100,000. Although the origin is most frequently cutaneous, mucosal melanoma has been described several times in literature, and despite its rarity (only 1% of all melanomas), increasing attention is being paid to this disease form. Within this subgroup, melanomas of the uropoetic apparatus are a rarity among rarities. Indeed, less than 50 cases of primary melanoma originating from the urinary bladder have been described, and even less originating from the kidney, renal pelvis and urethra. In this work, we present a detailed review of the literature related to this subclass of mucosal melanoma, delve into the biological landscape of this neoplasm and discuss current approaches, future perspectives and potential therapeutic approaches. Full article

The ability of tumor cells to evade apoptosis is established as one of the hallmarks of cancer. The deregulation of apoptotic pathways conveys a survival advantage enabling cancer cells to develop multi-drug resistance (MDR), a complex tumor phenotype referring to concurrent resistance toward agents with different function and/or structure. Proteins implicated in the intrinsic pathway of apoptosis, including the Bcl-2 superfamily and Inhibitors of Apoptosis (IAP) family members, as well as their regulator, tumor suppressor p53, have been implicated in the development of MDR in many cancer types. The PI₃K/AKT pathway is pivotal in promoting survival and proliferation and is often overactive in MDR tumors. In addition, the tumor microenvironment, particularly factors secreted by cancer-associated fibroblasts, can inhibit apoptosis in cancer cells and reduce the effectiveness of different anti-cancer drugs. In this review, we describe the main alterations that occur in apoptosis-and related pathways to promote MDR. We also summarize the main therapeutic approaches against resistant tumors, including agents targeting Bcl-2 family members, small molecule inhibitors against IAPs or AKT and agents of natural origin that may be used as monotherapy or in combination with conventional therapeutics. Finally, we highlight the potential of therapeutic exploitation of epigenetic modifications to reverse the MDR phenotype. Full article

Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with more than 2 million new cases in 2020. Its incidence and death rates have increased over the last three decades due to the change in risk factor profiles, better cancer registration, and cancer detection. The number of risk factors of BC is significant and includes both the modifiable factors and non-modifiable factors. Currently, about 80% of patients with BC are individuals aged >50. Survival depends on both stage and molecular subtype. Invasive BCs comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. Based on mRNA gene expression levels, BC can be divided into molecular subtypes (Luminal A, Luminal B, HER2-enriched, and basal-like). The molecular subtypes provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. The eighth edition of TNM classification outlines a new staging system for BC that, in addition to anatomical features, acknowledges biological factors. Treatment of breast cancer is complex and involves a combination of different modalities including surgery, radiotherapy, chemotherapy, hormonal therapy, or biological therapies delivered in diverse sequences. Full article

Tumor growth causes cancer cells to become hypoxic. A hypoxic condition is a hallmark of cancer. Metabolism of cancer cells differs from metabolism of normal cells. Cancer cells prefer the process of glycolysis as a source of ATP. Process of glycolysis generates only two molecules of ATP per one molecule of glucose, whereas the complete oxidative breakdown of one molecule of glucose yields 36 molecules of ATP. Therefore, cancer cells need more molecules of glucose in comparison with normal cells. Increased uptake of glucose by these cells is due to overexpression of glucose transporters, especially GLUT1 and GLUT3, that are hypoxia responsive, as well as other glucose transport proteins. Increased expression of these carrier proteins may be used in anticancer therapy. This phenomenon is used in diagnostic techniques such as FDG-PET. It is also suggested, and there are observations, that therapeutic inhibition of glucose transporters may be a method in treatment of cancer patients. On the other hand, there are described cases, in which upregulation of glucose transporters, as, for example, NIS, which is used in radioiodine therapy, can help patients with cancer. The aim of this review is the presentation of possibilities, and how glucose transporters can be used in anticancer therapy. Full article

The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumour cells. A multi-level impairment, involving mutation and genetic alteration, aberrant regulation of miRNAs sequences, and abnormal phosphorylation of cascade factors, has been found in multiple cancer types. The deregulation of this pathway counteracts common therapeutic strategies and contributes to multidrug resistance. In this review, we underline the involvement of this pathway in patho-physiological cell survival mechanisms, emphasizing its key role in the development of drug resistance. We also provide an overview of the potential inhibition strategies currently available. Full article

Colorectal cancer (CRC) mortality is mainly caused by patient refractoriness to common anti-cancer therapies and consequent metastasis formation. Besides, the notorious toxic side effects of chemotherapy are a concurrent obstacle to be tackled. Thus, new treatment approaches are needed to effectively improve patient outcomes. Compelling evidence demonstrated that cancer stem cells (CSCs) are responsible for treatment failure and relapse. New natural treatment approaches showed capabilities to selectively target the CSC subpopulation by rendering them targetable by standard cytotoxic compounds. Herein we show the anti-cancer properties of the polymethoxyflavones and prenylflavonoids extracted from Citrus sinensis and Humulus lupulus, respectively. The natural biofunctional fractions, singularly and in combination, reduced the cell viability of CRC stem cells (CR-CSCs) and synergized with 5-fluorouracil and oxaliplatin (FOX) chemotherapy. These phenomena were accompanied by a reduced S and G2/M phase of the cell cycle and upregulation of cell death-related genes. Notably, both phytoextracts in combination with FOX thwarted stemness features in CR-CSCs as demonstrated by the impaired clonogenic potential and decreased Wnt pathway activation. Extracts lowered the expression of CD44v6 and affected the expansion of metastatic CR-CSCs in patients refractory to chemotherapy. Together, this study highlights the importance of polymethoxyflavones and prenylflavonoids as natural remedies to aid oncological therapies. Full article

Chronic inflammation contributes to the malignant transformation of several malignancies and is an important component of breast cancer. The role of chronic inflammation in the initiation and development of breast cancer from normal breast tissue, however, is unclear and needs to be clarified. A review of the literature was conducted to define the chronic inflammatory processes in normal breast tissue at risk for breast cancer and in breast cancer, including the role of lymphocyte and macrophage infiltrates, chronic active adipocytes and fibroblasts, and processes that may promote chronic inflammation including the microbiome and factors related to genomic abnormalities and cellular injury. The findings indicate that in healthy normal breast tissue there is systemic evidence to suggest inflammatory changes are present and associated with breast cancer risk, and adipocytes and crown-like structures in normal breast tissue may be associated with chronic inflammatory changes. The microbiome, genomic abnormalities, and cellular changes are present in healthy normal breast tissue, with the potential to elicit inflammatory changes, while infiltrating lymphocytes are uncommon in these tissues. Chronic inflammatory changes occur prominently in breast cancer tissues, with important contributions from tumor-infiltrating lymphocytes and tumor-associated macrophages, cancer-associated adipocytes and crown-like structures, and cancer-associated fibroblasts, while the microbiome and DNA damage may serve to promote inflammatory events. Together, these findings suggest that chronic inflammation may play a role in influencing the initiation, development and conduct of breast cancer, although several chronic inflammatory processes in breast tissue may occur later in breast carcinogenesis. Full article

Despite the significant advancement in therapeutic strategies, breast, colorectal, gastric, lung, liver, and prostate cancers remain the most prevalent cancers in terms of incidence and mortality worldwide. The major causes ascribed to these burdens are lack of early diagnosis, high metastatic tendency, and drug resistance. Therefore, exploring reliable early diagnostic and prognostic biomarkers universal to most cancer types is a clinical emergency. Consequently, in the present study, the differentially expressed genes (DEGs) from the publicly available microarray datasets of six cancer types (liver, lung colorectal, gastric, prostate, and breast cancers), termed hub cancers, were analyzed to identify the universal DEGs, termed hub genes. Gene set enrichment analysis (GSEA) and KEGG mapping of the hub genes suggested their crucial involvement in the tumorigenic properties, including distant metastases, treatment failure, and survival prognosis. Notably, our results suggested high frequencies of genetic and epigenetic alterations of the DEGs in association with tumor staging, immune evasion, poor prognosis, and therapy resistance. Translationally, we intended to identify a drug candidate with the potential for targeting the hub genes. Using a molecular docking platform, we estimated that ovatodiolide, a bioactive anti-cancer phytochemical, has high binding affinities to the binding pockets of the hub genes. Collectively, our results suggested that the hub genes were associated with establishing an immune-suppressive tumor microenvironment favorable for disease progression and promising biomarkers for the early diagnosis and prognosis in multiple cancer types and could serve as potential druggable targets for ovatodiolide. Full article

The tumor immune microenvironment, including hepatocellular carcinoma (HCC), is complex, consisting of crosstalk among tumor components such as the cancer cells, stromal cells and immune cells. It is conceivable that phenotypic changes in cancer cells by genetic and epigenetic alterations affect the cancer–stroma interaction and anti-cancer immunity through the expression of immune checkpoint molecules, growth factors, cytokines, chemokines and metabolites that may act on the immune system in tumors. Therefore, predicting the outcome of ICI therapy requires a thorough understanding of the oncogenic signaling pathways in cancer and how they affect tumor immune evasion. In this review, we have detailed how oncogenic signaling pathways can play a role in altering the condition of the cellular components of the tumor immune microenvironment such as tumor-associated macrophages, regulatory T cells and myeloid-derived suppressor cells. The RAS/MAPK, PI3K/Akt, Wnt/β-catenin and JAK/STAT pathways have all been implicated in anti-tumor immunity. We also found that factors that reflect the immune microenvironment of the tumor, including the status of oncogenic pathways such as the volume of tumor-infiltrating T cells, expression of the immune checkpoint protein PD-1 and its ligand PD-L1, and activation of the Wnt/β-catenin signaling pathway, predict a response to ICI therapy in HCC cases. Full article

Pyroptosis is an inflammatory form of programmed cell death that is mediated by pore-forming proteins such as the gasdermin family (GSDMs), including GSDMA-E. Upon cleavage by activated caspases or granzyme proteases, the N-terminal of GSDMs oligomerizes in membranes to form pores, resulting in pyroptosis. Though all the gasdermin proteins have been studied in cancer, the role of pyroptosis in cancer remains mysterious, with conflicting findings. Numerous studies have shown that various stimuli, such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and chemotherapeutic drugs, could trigger pyroptosis when the cells express GSDMs. However, it is not clear whether pyroptosis in cancer induced by chemotherapeutic drugs or CAR T cell therapy is beneficial or harmful for anti-tumor immunity. This review discusses the discovery of pyroptosis as well as its role in inflammatory diseases and cancer, with an emphasis on tumor immunity. Full article

Photodynamic therapy (PDT) is a cancer treatment with strong potential over well-established standard therapies in certain cases. Non-ionising radiation, localisation, possible repeated treatments, and stimulation of immunological response are some of the main beneficial features of PDT. Despite the great potential, its application remains challenging. Limited light penetration depth, non-ideal photosensitisers, complex dosimetry, and complicated implementations in the clinic are some limiting factors hindering the extended use of PDT. To surpass actual technological paradigms, radically new sources, light-based devices, advanced photosensitisers, measurement devices, and innovative application strategies are under extensive investigation. The main aim of this review is to highlight the advantages/pitfalls, technical challenges and opportunities of PDT, with a focus on technologies for light activation of photosensitisers, such as light sources, delivery devices, and systems. In this vein, a broad overview of the current status of superficial, interstitial, and deep PDT modalities—and a critical review of light sources and their effects on the PDT process—are presented. Insight into the technical advancements and remaining challenges of optical sources and light devices is provided from a physical and bioengineering perspective. Full article

Extracellular vesicles (EVs) are crucial elements that sustain the communication between tumor cells and their microenvironment, and have emerged as a widespread mechanism of tumor formation and metastasis. In obesity, the adipose tissue becomes hypertrophic and hyperplastic, triggering increased production of pro-inflammatory adipokines, such as tumor necrosis factor α, interleukin 6, interleukin 1, and leptin. Furthermore, obese adipose tissue undergoes dysregulation in the cargo content of the released EVs, resulting in an increased content of pro-inflammatory proteins, fatty acids, and oncogenic microRNAs. These alterations drive obesity-associated inflammatory responses both locally and systemically. After being ignored for a long time, adipose tissues have recently received considerable attention as a major player in tumor microenvironment-linked obesity and cancer. The role of adipose tissue in the establishment and progression of cancer is reinforced by its high plasticity and inflammatory content. Such a relationship may be established by direct contact between adipocytes and cancer cells within the microenvironment or systemically, via EV-mediated cell-to-cell communication. Here, we highlight cues evidencing the influence of adipose tissue-derived EVs on the hallmarks of cancer, which are critical for tumor malignancy. Full article

Carcinogenesis is a multi-step process that refers to transformation of a normal cell into a tumoral neoplastic cell. The mechanisms that promote tumor initiation, promotion and progression are varied, complex and remain to be understood. Studies have highlighted the involvement of oncogenic mutations, genomic instability and epigenetic alterations as well as metabolic reprogramming, in different processes of oncogenesis. However, the underlying mechanisms still have to be clarified. Mitochondria are central organelles at the crossroad of various energetic metabolisms. In addition to their pivotal roles in bioenergetic metabolism, they control redox homeostasis, biosynthesis of macromolecules and apoptotic signals, all of which are linked to carcinogenesis. In the present review, we discuss how mitochondria contribute to the initiation of carcinogenesis through gene mutations and production of oncometabolites, and how they promote tumor progression through the control of metabolic reprogramming and mitochondrial dynamics. Finally, we present mitochondrial metabolism as a promising target for the development of novel therapeutic strategies. Full article

The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. High abundance of EGFR and large internal deletions are frequently observed in brain tumors, whereas point mutations and small insertions within the kinase domain are common in lung cancer. For these reasons EGFR and its preferred heterodimer partner, HER2/ERBB2, became popular targets of anti-cancer therapies. Nevertheless, EGFR research keeps revealing unexpected observations, which are reviewed herein. Once activated by a ligand, EGFR initiates a time-dependent series of molecular switches comprising downregulation of a large cohort of microRNAs, up-regulation of newly synthesized mRNAs, and covalent protein modifications, collectively controlling phenotype-determining genes. In addition to microRNAs, long non-coding RNAs and circular RNAs play critical roles in EGFR signaling. Along with driver mutations, EGFR drives metastasis in many ways. Paracrine loops comprising tumor and stromal cells enable EGFR to fuel invasion across tissue barriers, survival of clusters of circulating tumor cells, as well as colonization of distant organs. We conclude by listing all clinically approved anti-cancer drugs targeting either EGFR or HER2. Because emergence of drug resistance is nearly inevitable, we discuss the major evasion mechanisms. Full article

The interrogation of intrinsic and adaptive resistance to cancer immunotherapy has identified lack of antigen presentation and type I interferon signaling as biomarkers of non-T-cell-inflamed tumors and clinical progression. A myriad of pre-clinical studies have implicated the cGAS/stimulator of interferon genes (STING) pathway, a cytosolic DNA-sensing pathway that drives activation of type I interferons and other inflammatory cytokines, in the host immune response against tumors. The STING pathway is also increasingly understood to have other anti-tumor functions such as modulation of the vasculature and augmentation of adaptive immunity via the support of tertiary lymphoid structure development. Many natural and synthetic STING agonists have entered clinical development with the first generation of intra-tumor delivered cyclic dinucleotides demonstrating safety but only modest systemic activity. The development of more potent and selective STING agonists as well as novel delivery systems that would allow for sustained inflammation in the tumor microenvironment could potentially augment response rates to current immunotherapy approaches and overcome acquired resistance. In this review, we will focus on the latest developments in STING-targeted therapies and provide an update on the clinical development and application of STING agonists administered alone, or in combination with immune checkpoint blockade or other approaches. Full article

The discovery of microRNAs (miRNAs) in 1993 has challenged the dogma of gene expression regulation. MiRNAs affect most of cellular processes from metabolism, through cell proliferation and differentiation, to cell death. In cancer, deregulated miRNA expression leads to tumor development and progression by promoting acquisition of cancer hallmark traits. The multi-target action of miRNAs, which enable regulation of entire signaling networks, makes them attractive tools for the development of anti-cancer therapies. Hence, supplementing downregulated miRNA by synthetic oligonucleotides or silencing overexpressed miRNAs through artificial antagonists became a common strategy in cancer research. However, the ultimate success of miRNA therapeutics will depend on solving pharmacokinetic and targeted delivery issues. The development of a number of nanocarrier-based platforms holds significant promises to enhance the cell specific controlled delivery and safety profile of miRNA-based therapies. In this review, we provide among the most comprehensive assessments to date of promising nanomedicine platforms that have been tested preclinically, pertaining to the treatment of selected solid tumors including lung, liver, breast, and glioblastoma tumors as well as endocrine malignancies. The future challenges and potential applications in clinical oncology are discussed. Full article

Metronomic chemotherapy treatment (mCHT) refers to the chronic administration of low doses chemotherapy that can sustain prolonged, and active plasma levels of drugs, producing favorable tolerability and it is a new promising therapeutic approach in solid and in hematologic tumors. mCHT has not only a direct effect on tumor cells, but also an action on cell microenvironment, by inhibiting tumor angiogenesis, or promoting immune response and for these reasons can be considered a multi-target therapy itself. Here we review the state of the art of mCHT use in some classical tumour types, such as breast and no small cell lung cancer (NSCLC), see what is new regarding most recent data in different cancer types, such as glioblastoma (GBL) and acute myeloid leukemia (AML), and new drugs with potential metronomic administration. Finally, a look at the strategic use of mCHT in the context of health emergencies, or in low –and middle-income countries (LMICs), where access to adequate healthcare is often not easy, is mandatory, as we always need to bear in in mind that equity in care must be a compulsory part of our medical work and research. Full article

DPP-4/CD26, a membrane-bound glycoprotein, is ubiquitously expressed and has diverse biological functions. Because of its enzymatic action, such as the degradation of incretin hormones, DPP-4/CD26 is recognized as the significant therapeutic target for type 2 diabetes (T2DM); DPP-4 inhibitors have been used as an anti-diabetic agent for a decade. The safety profile of DPP-4 inhibitors for a cardiovascular event in T2DM patients has been widely analyzed; however, a clear association between DPP-4 inhibitors and tumor biology is not yet established. Previous preclinical studies reported that DPP-4 suppression would impact tumor progression processes. With regard to this finding, we have shown that the DPP-4 inhibitor induces breast cancer metastasis and chemoresistance via an increase in its substrate C-X-C motif chemokine 12, and the consequent induction of epithelial-mesenchymal transition in the tumor. DPP-4/CD26 plays diverse pivotal roles beyond blood glucose control; thus, DPP-4 inhibitors can potentially impact cancer-bearing T2DM patients either favorably or unfavorably. In this review, we primarily focus on the possible undesirable effect of DPP-4 inhibition on tumor biology. Clinicians should note that the safety of DPP-4 inhibitors for diabetic patients with an existing cancer is an unresolved issue, and further mechanistic analysis is essential in this field. Full article

Recently, the liquid biopsy (LB), a non-invasive and easy to repeat approach, has started to compete with the tissue biopsy (TB) for detection of targets for administration of therapeutic strategies for patients with advanced stages of lung cancer at tumor progression. A LB at diagnosis of late stage non-small cell lung carcinoma (NSCLC) is also being performed. It may be asked if a LB can be complementary (according to the clinical presentation or systematics) or even an alternative to a TB for treatment-naïve advanced NSCLC patients. Nucleic acid analysis with a TB by next-generation sequencing (NGS) is gradually replacing targeted sequencing methods for assessment of genomic alterations in lung cancer patients with tumor progression, but also at baseline. However, LB is still not often used in daily practice for NGS. This review addresses different aspects relating to the use of LB for NGS at diagnosis in advanced NSCLC, including its advantages and limitations. Full article

The tumor microenvironment (TME) regulates essential tumor survival and promotion functions. Interactions between the cellular and structural components of the TME allow cancer cells to become invasive and disseminate from the primary site to distant locations, through a complex and multistep metastatic cascade. Tumor-associated M2-type macrophages have growth-promoting and immunosuppressive functions; mesenchymal cells mass produce exosomes that increase the migratory ability of cancer cells; cancer associated fibroblasts (CAFs) reorganize the surrounding matrix creating migration-guiding tracks for cancer cells. In addition, the tumor extracellular matrix (ECM) exerts determinant roles in disease progression and cancer cell migration and regulates therapeutic responses. The hypoxic conditions generated at the primary tumor force cancer cells to genetically and/or epigenetically adapt in order to survive and metastasize. In the circulation, cancer cells encounter platelets, immune cells, and cytokines in the blood microenvironment that facilitate their survival and transit. This review discusses the roles of different cellular and structural tumor components in regulating the metastatic process, targeting approaches using small molecule inhibitors, nanoparticles, manipulated exosomes, and miRNAs to inhibit tumor invasion as well as current and future strategies to remodel the TME and enhance treatment efficacy to block the detrimental process of metastasis. Full article

Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the development of tools that help us in the early diagnosis, treatment selection, disease monitoring, evaluation of the response and prognosis. Liquid biopsy (LB), in its different modalities, represents a particularly interesting tool for these purposes, since it is a minimally invasive and risk-free procedure that can detect both the presence of genetic material from the tumor and circulating tumor cells (CTCs) in the blood and therefore distantly reflect the global status of the disease. In this work we review the current status of the main LB modalities (ctDNA, exosomes, CTCs and cfRNAs) for detecting and monitoring PDAC. Full article

In cancer cells, a vital cellular process during metastasis is the transformation of epithelial cells towards motile mesenchymal cells called the epithelial to mesenchymal transition (EMT). The cytoskeleton is an active network of three intracellular filaments: actin cytoskeleton, microtubules, and intermediate filaments. These filaments play a central role in the structural design and cell behavior and are necessary for EMT. During EMT, epithelial cells undergo a cellular transformation as manifested by cell elongation, migration, and invasion, coordinated by actin cytoskeleton reorganization. The actin cytoskeleton is an extremely dynamic structure, controlled by a balance of assembly and disassembly of actin filaments. Actin-binding proteins regulate the process of actin polymerization and depolymerization. Microtubule reorganization also plays an important role in cell migration and polarization. Intermediate filaments are rearranged, switching to a vimentin-rich network, and this protein is used as a marker for a mesenchymal cell. Hence, targeting EMT by regulating the activities of their key components may be a potential solution to metastasis. This review summarizes the research done on the physiological functions of the cytoskeleton, its role in the EMT process, and its effect on multidrug-resistant (MDR) cancer cells—highlight some future perspectives in cancer therapy by targeting cytoskeleton. Full article

Lung cancer is the most common cause of cancer-related death worldwide, and the prognosis for stage IV remains poor. The presence of genetic alterations in tumor cells, such as EGFR and BRAF gene mutations, as well as ALK and ROS1 gene rearrangements, are indications for targeted therapies. Many such treatments are already registered and used on a wide scale. In comparison to standard chemotherapy, they can prolong not only progression-free survival but also overall survival. Moreover, they are able to provide excellent quality of life and rapid improvement of cancer-related symptoms such as dyspnea, cough and pain. Recent years have witnessed great advances in both molecular diagnostics and new molecular therapies for non-small-cell lung cancer. This review presents new therapeutic targets in NSCLC, as well as drugs of which the activity against NTRK, RET, MET or HER2 gene alterations (including EGFR exon 20 insertions) has either been confirmed or is currently being evaluated. Although these particular genetic alterations in NSCLC are generally rare, each accounting for 1–2% of patients, in total about half of all patients have molecular alterations and may ultimately receive targeted therapies. Full article

The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system. Full article

Glioblastoma (GBM), the most frequent and aggressive glial tumor, is currently treated as first line by the Stupp protocol, which combines, after surgery, radiotherapy and chemotherapy. For recurrent GBM, in absence of standard treatment or available clinical trials, various protocols including cytotoxic drugs and/or bevacizumab are currently applied. Despite these heavy treatments, the mean overall survival of patients is under 18 months. Many clinical studies are underway. Based on clinicaltrials.org and conducted up to 1 April 2020, this review lists, not only main, but all targeted therapies in phases II-IV of 257 clinical trials on adults with newly diagnosed or recurrent GBMs for the last twenty years. It does not involve targeted immunotherapies and therapies targeting tumor cell metabolism, that are well documented in other reviews. Without surprise, the most frequently reported drugs are those targeting (i) EGFR (40 clinical trials), and more generally tyrosine kinase receptors (85 clinical trials) and (ii) VEGF/VEGFR (75 clinical trials of which 53 involving bevacizumab). But many other targets and drugs are of interest. They are all listed and thoroughly described, on an one-on-one basis, in four sections related to targeting (i) GBM stem cells and stem cell pathways, (ii) the growth autonomy and migration, (iii) the cell cycle and the escape to cell death, (iv) and angiogenesis. Full article

Osteosarcoma is the most frequent primary bone cancer, mainly affecting those of young ages. Although surgery combined with cytotoxic chemotherapy has significantly increased the chances of cure, recurrent and refractory disease still impose a tough therapeutic challenge. We performed a systematic literature review of the available clinical evidence, regarding treatment of recurrent and/or refractory osteosarcoma over the last two decades. Among the 72 eligible studies, there were 56 prospective clinical trials, primarily multicentric, single arm, phase I or II and non-randomized. Evaluated treatment strategies included cytotoxic chemotherapy, tyrosine kinase and mTOR inhibitors and other targeted agents, as well as immunotherapy and combinatorial approaches. Unfortunately, most treatments have failed to induce objective responses, albeit some of them may sustain disease control. No driver mutations have been recognized, to serve as effective treatment targets, and predictive biomarkers of potential treatment effectiveness are lacking. Hopefully, ongoing and future clinical and preclinical research will unlock the underlying biologic mechanisms of recurrent and refractory osteosarcoma, expanding the therapeutic choices available to pre-treated osteosarcoma patients. Full article

Hepatocellular carcinoma (HCC) is a leading cause of global cancer death. Major etiologies of HCC relate to chronic viral infections as well as metabolic conditions. The survival rate of people with HCC is very low and has been attributed to late diagnosis with limited treatment options. Combining ultrasound and the biomarker alpha-fetoprotein (AFP) is currently one of the most widely used screening combinations for HCC. However, the clinical utility of AFP is controversial, and the frequency and operator-dependence of ultrasound lead to a variable degree of sensitivity and specificity across the globe. In this review, we summarize recent developments in the search for non-invasive serum biomarkers for early detection of HCC to improve prognosis and outcome for patients. We focus on tumor-associated protein markers, immune mediators (cytokines and chemokines), and micro-RNAs in serum or circulating extracellular vesicles and examine their potential for clinical application. Full article

O-linked β-N-acetylglucosamine (O-GlcNAc) is a single sugar post-translational modification (PTM) of intracellular proteins linking nutrient flux through the Hexosamine Biosynthetic Pathway (HBP) to the control of cis-regulatory elements in the genome. Aberrant O-GlcNAcylation is associated with the development, progression, and alterations in gene expression in cancer. O-GlcNAc cycling is defined as the addition and subsequent removal of the modification by O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA) provides a novel method for cells to regulate various aspects of gene expression, including RNA polymerase function, epigenetic dynamics, and transcription factor activity. We will focus on the complex relationship between phosphorylation and O-GlcNAcylation in the regulation of the RNA Polymerase II (RNAP II) pre-initiation complex and the regulation of the carboxyl-terminal domain of RNAP II via the synchronous actions of OGT, OGA, and kinases. Additionally, we discuss how O-GlcNAcylation of TATA-box binding protein (TBP) alters cellular metabolism. Next, in a non-exhaustive manner, we will discuss the current literature on how O-GlcNAcylation drives gene transcription in cancer through changes in transcription factor or chromatin remodeling complex functions. We conclude with a discussion of the challenges associated with studying O-GlcNAcylation and present several new approaches for studying O-GlcNAc regulated transcription that will advance our understanding of the role of O-GlcNAc in cancer. Full article

The epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, being responsible in many cases for the onset of the metastatic cascade and being integral in the ability of cells to resist drug treatment. Most studies of EMT focus on its induction via chemical signals such as TGF-β or Notch ligands, but it has become increasingly clear that biomechanical features of the microenvironment such as extracellular matrix (ECM) stiffness can be equally important. Here, we introduce a coupled feedback loop connecting stiffness to the EMT transcription factor ZEB1, which acts via increasing the secretion of LOXL2 that leads to increased cross-linking of collagen fibers in the ECM. This increased cross-linking can effectively increase ECM stiffness and increase ZEB1 levels, thus setting a positive feedback loop between ZEB1 and ECM stiffness. To investigate the impact of this non-cell-autonomous effect, we introduce a computational approach capable of connecting LOXL2 concentration to increased stiffness and thereby to higher ZEB1 levels. Our results indicate that this positive feedback loop, once activated, can effectively lock the cells in a mesenchymal state. The spatial-temporal heterogeneity of the LOXL2 concentration and thus the mechanical stiffness also has direct implications for migrating cells that attempt to escape the primary tumor. Full article

Immunotherapy is presently one of the most promising areas of investigation and development for the treatment of cancer. While immune checkpoint-blocking monoclonal antibodies and chimeric antigen receptor (CAR) T-cell-based therapy have recently provided in some cases valuable therapeutic options, the goal of cure has not yet been achieved for most malignancies and more efforts are urgently needed. Noncoding RNAs (ncRNA), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), regulate several biological processes via selective targeting of crucial molecular signaling pathways. Recently, the key roles of miRNA and lncRNAs as regulators of the immune-response in cancer have progressively emerged, since they may act (i) by shaping the intrinsic tumor cell and microenvironment (TME) properties; (ii) by regulating angiogenesis, immune-escape, epithelial-to-mesenchymal transition, invasion, and drug resistance; and (iii) by acting as potential biomarkers for prognostic assessment and prediction of response to immunotherapy. In this review, we provide an overview on the role of ncRNAs in modulating the immune response and the TME. We discuss the potential use of ncRNAs as potential biomarkers or as targets for development or clinical translation of new therapeutics. Finally, we discuss the potential combinatory approaches based on ncRNA targeting agents and tumor immune-checkpoint inhibitor antibodies or CAR-T for the experimental treatment of human cancer. Full article

Multiple myeloma is the second most common hematologic malignancy. Current treatment strategies are mainly based on immunomodulatory drugs, proteasome inhibitors or combination of both. Novel agents added to these backbone treatments represent a promising strategy in treatment of newly diagnosed as well as relapsed and refractory multiple myeloma patients. In this respect, the incorporation of monoclonal antibodies into standard-of-care regimens markedly improved prognosis of myeloma patients during the last years. More specifically, monoclonal anti-CD38 antibodies, daratumumab and isatuximab, have been implemented into treatment strategies from first-line treatment to refractory disease. In addition, the monoclonal anti-SLAM-F7 antibody elotuzumab in combination with immunomodulatory drugs has improved the clinical outcomes of patients with relapsed/refractory disease. Belantamab mafodotin is the first approved antibody drug conjugate directed against B cell maturation antigen and is currently used as a monotherapy for patients with advanced disease. This review focuses on clinical efficacy and safety of monoclonal antibodies as well as antibody drug conjugates in multiple myeloma. Full article

Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin–proteasome pathway. Notably, aminopeptidases can be utilized in the delivery of antibody and peptide-conjugated drugs, such as melflufen, currently in clinical trials. We analyzed the expression of 39 aminopeptidase genes in MM samples from 122 patients treated at Finnish cancer centers and 892 patients from the CoMMpass database. Based on ranked abundance, LAP3, ERAP2, METAP2, TTP2, and DPP7 were highly expressed in MM. ERAP2, XPNPEP1, DPP3, RNPEP, and CTSV were differentially expressed between relapsed/refractory and newly diagnosed MM samples (p < 0.05). Sensitivity to melflufen was detected ex vivo in 11/15 MM patient samples, and high sensitivity was observed, especially in relapsed/refractory samples. Survival analysis revealed that high expression of XPNPEP1, RNPEP, DPP3, and BLMH (p < 0.05) was associated with shorter overall survival. Hydrolysis analysis demonstrated that melflufen is a substrate for aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP. The sensitivity of MM cell lines to melflufen was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM. Full article

The ubiquitin proteasome system (UPS) governs the non-lysosomal degradation of oxidized, damaged, or misfolded proteins in eukaryotic cells. This process is tightly regulated through the activation and transfer of polyubiquitin chains to target proteins which are then recognized and degraded by the 26S proteasome complex. The role of UPS is crucial in regulating protein levels through degradation to maintain fundamental cellular processes such as growth, division, signal transduction, and stress response. Dysregulation of the UPS, resulting in loss of ability to maintain protein quality through proteolysis, is closely related to the development of various malignancies and tumorigenesis. Here, we provide a comprehensive general overview on the regulation and roles of UPS and discuss functional links of dysregulated UPS in human malignancies. Inhibitors developed against components of the UPS, which include U.S. Food and Drug Administration FDA-approved and those currently undergoing clinical trials, are also presented in this review. Full article

Tissue functionality and integrity demand continuous changes in distribution of major components in the extracellular matrices (ECMs) under normal conditions aiming tissue homeostasis. Major matrix degrading proteolytic enzymes are matrix metalloproteinases (MMPs), plasminogen activators, atypical proteases such as intracellular cathepsins and glycolytic enzymes including heparanase and hyaluronidases. Matrix proteases evoke epithelial-to-mesenchymal transition (EMT) and regulate ECM turnover under normal procedures as well as cancer cell phenotype, motility, invasion, autophagy, angiogenesis and exosome formation through vital signaling cascades. ECM remodeling is also achieved by glycolytic enzymes that are essential for cancer cell survival, proliferation and tumor progression. In this article, the types of major matrix remodeling enzymes, their effects in cancer initiation, propagation and progression as well as their pharmacological targeting and ongoing clinical trials are presented and critically discussed. Full article

Immune checkpoint inhibitors (ICIs) have obtained durable responses in many cancers, making it possible to foresee their potential in improving the health of cancer patients. However, immunotherapies are currently limited to a minority of patients and there is a need to develop a better understanding of the basic molecular mechanisms and functions of pivotal immune regulatory molecules. Immune checkpoint cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and regulatory T (T_reg) cells play pivotal roles in hindering the anticancer immunity. T_reg cells suppress antigen-presenting cells (APCs) by depleting immune stimulating cytokines, producing immunosuppressive cytokines and constitutively expressing CTLA-4. CTLA-4 molecules bind to CD80 and CD86 with a higher affinity than CD28 and act as competitive inhibitors of CD28 in APCs. The purpose of this review is to summarize state-of-the-art understanding of the molecular mechanisms underlining CTLA-4 immune regulation and the correlation of the ICI response with CTLA-4 expression in T_reg cells from preclinical and clinical studies for possibly improving CTLA-4-based immunotherapies, while highlighting the knowledge gap. Full article

In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics. Full article

Age is one of the main risk factors of cancer; several biological changes linked with the aging process can explain this. As our population is progressively aging, the proportion of older patients with cancer is increasing significantly. Due to the heterogeneity of general health and functional status amongst older persons, treatment of cancer is a major challenge in this vulnerable population. Older patients often experience more side effects of anticancer treatments. Over-treatment should be avoided to ensure an optimal quality of life. On the other hand, under-treatment due to fear of toxicity is a frequent problem and can lead to an increased risk of relapse and worse survival. There is a delicate balance between benefits of therapy and risk of toxicity. Robust biomarkers that reflect the body’s biological age may aid in outlining optimal individual treatment regimens for older patients with cancer. In particular, the impact of age on systemic immunity and the tumor immune infiltrate should be considered, given the expanding role of immunotherapy in cancer treatment. In this review, we summarize current knowledge concerning the mechanistic connections between aging and cancer, as well as aging biomarkers that could be helpful in the field of geriatric oncology. Full article

Direct intralesional injection of specific or even generic agents, has been proposed over the years as cancer immunotherapy, in order to treat cutaneous or subcutaneous metastasis. Such treatments usually induce an effective control of disease in injected lesions, but only occasionally were able to demonstrate a systemic abscopal effect on distant metastases. The usual availability of tissue for basic and translational research is a plus in utilizing this approach, which has been used in primis for the treatment of locally advanced melanoma. Melanoma is an immunogenic tumor that could often spread superficially causing in-transit metastasis and involving draining lymph nodes, being an interesting model to study new drugs with different modality of administration from normal available routes. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for intratumoral injection, that produces granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhances local and systemic antitumor immune responses. After infection, selected viral replication happens in tumor cells leading to tumor cell lysis and activating a specific T-cell driven immune response. For this reason, a probable synergistic effect with immune checkpoints inhibition have been described. Pre-clinical studies in melanoma confirmed that T-VEC preferentially infects melanoma cells and exerts its antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has been assessed in monotherapy in Phase II and III clinical trials demonstrating a tolerable side-effect profile, a promising efficacy in both injected and uninjected lesions, but a mild effect at a systemic level. In fact, despite improved local disease control and a trend toward superior overall survival in respect to the comparator GM-CSF (which was injected subcutaneously daily for two weeks), responses as a single agent therapy have been uncommon in patients with visceral metastases. For this reason, T-VEC is currently being evaluated in combinations with other immune checkpoint inhibitors such as ipilimumab and pembrolizumab, with interesting confirmation of activity even systemically. Full article

CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased antigen presentation, maturation (licensing) of dendritic cells, and activation of CD8+ T cells. Here we analyzed gene expression data from The Cancer Genome Atlas in melanoma, renal cell carcinoma, and pancreatic adenocarcinoma and found correlations between CD40 and several genes involved in antigen presentation and T cell function, supporting further exploration of CD40 agonists to treat cancer. Agonist CD40 antibodies have induced anti-tumor effects in several tumor models and the effect has been more pronounced when used in combination with other treatments (immune checkpoint inhibition, chemotherapy, and colony-stimulating factor 1 receptor inhibition). The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies. Full article

The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins (BIM, BAD, NOXA, PUMA, BID, BIK, HRK). Notably, the BCL-2 antiapoptotic proteins are often overexpressed in malignant cells. While this offers survival advantages to malignant cells and strengthens their drug resistance capacity, it also offers opportunities for novel targeted therapies that selectively kill such cells. This review provides a comprehensive overview of the extensive preclinical and clinical studies targeting BCL-2 proteins with various BCL-2 proteins inhibitors with emphasis on venetoclax as a single agent, as well as in combination with other therapeutic agents. This review also discusses recent advances, challenges focusing on drug resistance, and future perspectives for effective targeting the Bcl-2 family of proteins in cancer. Full article

Cancer remains as the second leading cause of death, worldwide. Despite the enormous important advances observed in the last decades, advanced stages of the disease remain incurable. The severe side effects associated to systemic high doses of chemotherapy and the development of drug resistance impairs a safe and efficiency anticancer therapy. Therefore, new formulations are continuously under research and development to improve anticancer drugs therapeutic index through localized delivery at tumor sites. Among a wide range of possibilities, hydrogels have recently gained special attention due to their potential to allow in situ sustained and controlled anticancer drug release. In particular, stimuli-responsive hydrogels which are able to change their physical state from liquid to gel accordingly to external factors such as temperature, pH, light, ionic strength, and magnetic field, among others. Some of these formulations presented promising results for the localized control and treatment of cancer. The present work aims to discuss the main properties and application of stimuli-responsive hydrogels in cancer treatment and summarize the most important advances observed in the last decades focusing on the use of pH-, light-, ionic strength-, and magnetic-responsive hydrogels. Full article

Microsatellite instability (MSI) is a tumor phenotype related to a deficient DNA mismatch repair system (dMMR). This phenotype, observed in 5% of metastatic mCRC but 10–18% of localized CRC, is associated with high tumor mutational burden with highly immunogenic neoantigens. It has emerged as a major predictive biomarker for the efficacy of ICIs. In this review, we will present a comprehensive overview of the literature concerning the efficacy of ICIs in MSI/dMMR mCRC, with a focus on new developments in first-line metastatic setting. Then, we will present current and future challenges of immuno-oncology for patients with MSI/dMMR metastatic CRC. Full article

Immunotherapy by immune checkpoint inhibition has become a main pillar in the armamentarium to treat head and neck cancer and is based on the premise that the host immune system can be reactivated to successfully eliminate cancer cells. However, the response rate remains low and only a small subset of head and neck cancer patients achieves a durable clinical benefit. The availability of multi-omics data and emerging computational technologies facilitate not only a deeper understanding of the cellular composition in the tumor immune microenvironment but also enables the study of molecular principles in the complex regulation of immune surveillance versus tolerance. These knowledges will pave the way to apply immunotherapy more precisely and effectively. This review aims to provide a holistic view on how the immune landscape dictates the tumor fate and vice versa, and how integrative analysis of multi-omics data contribute to our current knowledge on the accuracy of predictive biomarkers and on a broad range of factors influencing the response to immunotherapy in head and neck cancer. Full article

Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes, myeloid cells and platelets, and Btk-inhibitors (BTKi) are used to treat patients with B-cell malignancies, developed against autoimmune diseases, have been proposed as novel antithrombotic drugs, and been tested in patients with severe COVID-19. However, mild bleeding is frequent in patients with B-cell malignancies treated with the irreversible BTKi ibrutinib and the recently approved 2nd generation BTKi acalabrutinib, zanubrutinib and tirabrutinib, and also in volunteers receiving in a phase-1 study the novel irreversible BTKi BI-705564. In contrast, no bleeding has been reported in clinical trials of other BTKi. These include the brain-penetrant irreversible tolebrutinib and evobrutinib (against multiple sclerosis), the irreversible branebrutinib, the reversible BMS-986142 and fenebrutinib (targeting rheumatoid arthritis and lupus erythematodes), and the reversible covalent rilzabrutinib (against pemphigus and immune thrombocytopenia). Remibrutinib, a novel highly selective covalent BTKi, is currently in clinical studies of autoimmune dermatological disorders. This review describes twelve BTKi approved or in clinical trials. By focusing on their pharmacological properties, targeted disease, bleeding side effects and actions on platelets it attempts to clarify the mechanisms underlying bleeding. Specific platelet function tests in blood might help to estimate the probability of bleeding of newly developed BTKi. Full article

Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization. Full article

Since human epidermal growth factor receptor-2 (HER2) characterization, going through clinical research and regulatory approval of HER2-targeted therapies, much has elapsed and is still unfolding. Hitherto, only breast cancer (BC) patients with HER2 immunohistochemistry 3+ or with HER2 gene fluorescence in-situ hybridization (FISH) amplification (a.k.a., HER2-positive BC) have benefited from anti-HER2 agents. In recent years, however, much of the research effort has been expanded, with positive outcomes being reached for formerly known HER2-negative BC that yet express HER2 to some degree (HER2 immunohistochemistry 1+ or 2+, but FISH negative) and are currently being classified as HER2-low BC for the purpose of trial enrollment. In this sense, our aim is to review the body of evidence of HER2-low BC that led to the study of first-generation anti-HER2 agents, like trastuzumab, and how they have failed to achieve any clinical applicability in this setting. In addition, we review new data that is leading to the growing success of the new generation of drugs, especially the promising HER2-directed antibody–drug conjugates. A narrative review is also performed regarding the rationale behind the consolidated and ongoing clinical trials studying anti-HER2 agents in combination with unrelated agents, such as immunotherapy, endocrine therapy, and CDK4/6 inhibitors. Hopefully, all this ongoing research effort will be able to extend the survival benefits seen with anti-HER2 agents in HER2-positive disease, at least to some degree, to the greater proportion of patients with HER2-low BC. Full article

Human colorectal cancers are mostly microsatellite-stable with no response to anti-PD-1 blockade immunotherapy, necessitating the development of a new immunotherapy. Osteopontin (OPN) is elevated in human colorectal cancer and may function as an immune checkpoint. We aimed at elucidating the mechanism of action of OPN and determining the efficacy of OPN blockade immunotherapy in suppression of colon cancer. We report here that OPN is primarily expressed in tumor cells, myeloid cells, and innate lymphoid cells in human colorectal carcinoma. Spp1 knock out mice exhibit a high incidence and fast growth rate of carcinogen-induced tumors. Knocking out Spp1 in colon tumor cells increased tumor-specific CTL cytotoxicity in vitro and resulted in decreased tumor growth in vivo. The OPN protein level is elevated in the peripheral blood of tumor-bearing mice. We developed four OPN neutralization monoclonal antibodies based on their efficacy in blocking OPN inhibition of T cell activation. OPN clones 100D3 and 103D6 increased the efficacy of tumor-specific CTLs in killing colon tumor cells in vitro and suppressed colon tumor growth in tumor-bearing mice in vivo. Our data indicate that OPN blockade immunotherapy with 100D3 and 103D6 has great potential to be further developed for colorectal cancer immunotherapy and for rendering a colorectal cancer response to anti-PD-1 immunotherapy. Full article

Fertility-sparing surgery (FSS) is increasingly being offered to women with a gynecological malignancy who wish to preserve fertility. In this systematic review, we evaluate the best evidence currently available on oncological and reproductive outcome after FSS for early stage cervical cancer, epithelial ovarian cancer, and endometrial cancer. An extensive literature search was conducted using the electronic databases Medline (OVID), Embase, and Cochrane Library to identify eligible studies published up to December 2020. In total, 153 studies were included with 7544, 3944, and 1229 patients who underwent FSS for cervical, ovarian, and endometrial cancer, respectively. We assessed the different FSS techniques that are available to preserve fertility, i.e., omitting removal of the uterine body and preserving at least one ovary. Overall, recurrence rates after FSS are reassuring and therefore, these conservative procedures seem oncologically safe in the current selection of patients with low-stage and low-grade disease. However, generalized conclusions should be made with caution due to the methodology of available studies, i.e., mostly retrospective cohort studies with a heterogeneous patient population, inducing selection bias. Moreover, about half of patients do not pursue pregnancy despite FSS and the reasons for these decisions have not yet been well studied. International collaboration will facilitate the collection of solid evidence on FSS and the related decision-making process to optimize patient selection and counseling. Full article

Cancer arises from mutations accruing within cancer cells, but the tumor microenvironment (TME) is believed to be a major, often neglected, factor involved in therapy resistance and disease progression. Cancer-associated fibroblasts (CAFs) are prominent and key components of the TME in most types of solid tumors. Extensive research over the past decade revealed their ability to modulate cancer metastasis, angiogenesis, tumor mechanics, immunosuppression, and drug access through synthesis and remodeling of the extracellular matrix and production of growth factors. Thus, they are considered to impede the response to current clinical cancer therapies. Therefore, targeting CAFs to counteract these protumorigenic effects, and overcome the resistance to current therapeutic options, is an appealing and emerging strategy. In this review, we discuss how CAFs affect prognosis and response to clinical therapy and provide an overview of novel therapies involving CAF-targeting agents in lung and pancreatic cancer. Full article