The treatment of colon cancer (CC) with chemotherapeutics presents significant burden for the patients due to high toxicity and relatively low response. The present review introduces recent updates on global incidence, mortality, screen approaches and adjuvant regimens as well as medicinal plant extracts and their marker compounds as adjuvants for CC. We present the cellular mechanisms and pathways that promote metastasis of CC cells and their colonization in the liver and lungs. This review describes a regulatory loop between the Wnt, Myc, and long non-coding RNAs in promoting metastasis of CC cells. It also identifies the anticancer effects of promising natural compounds mainly on CC cell lines, tumor-bearing animal models and in a clinical trial. This review describes the mechanisms of action of promising polyphenols, flavonoids, terpenes, and alkaloids in the modulation of the metastasis of CC cells to the liver and lung. We also present promising natural compounds that target the Wnt signaling and its target genes in CC. We report few animal and human clinical trials on natural compounds that are evaluated for mitigating CC. The relevance of natural compounds as an adjuvant in monotherapy or combination therapy of CC is discussed. Overall, we provide an overview of natural compounds in CC therapy with future directions.
Colon cancer (CC) is the third most common cancer diagnosed worldwide, making it a serious global challenge. Metastasis is mainly responsible for high mortality in CC patients. In CC patients, a mutation in Kirsten rat sarcoma (KRAS), adenomatous polyposis coli (APC), and tumor protein 53 (TP53) mainly drives the metastasis, mediates drug resistance, and promotes tumor recurrence by maintaining stem cell phenotype. Recently, long noncoding RNAs (lncRNAs) were reported to mediate KRAS-, APC-, and TP53-dependent CC progression and metastasis. In the present review, we have discussed the current updates on lncRNAs dependent on KRAS, APC, and TP53 in CC progression and metastasis. We also presented current trends in targeted therapies, immune therapies, redox-based therapies, and phytochemical-based therapies for CC. Finally, nanosystems for targeted delivery of therapeutic agents, which limit drug resistance and drug toxicities, were discussed. Therefore, targeted therapeutics can be used for CC treatment at the clinical stage.
Lung cancer (LC) represents a global threat, being the deadliest tumor worldwide. A new hope comes from the immune-checkpoint inhibitors (ICIs), a novel therapeutic approach which reactivates the immune system against the cancer cells. ICIs are antibodies targeting the immune checkpoints and triggering T cells to actively recognize and eliminate malignant cells. Despite their demonstrated efficacy within a portion of LC patients, ICIs show some limitations. One is the potential development of resistance to therapy and tumor recurrence over time. The second one consists in the potential manifestation of immune-related adverse events which can be severe or even fatal. The research is currently working at a fast pace to identify novel biomarkers to tackle LC patients who may truly benefit from ICI-based therapy. Among the proposed source of biomarkers, lung and gut microbiota are currently studied. In this review, all of the up-to-date knowledge concerning the relationship occurring between the airways/gastrointestinal microbiota and LC genesis, development, as well as response to ICIs is discussed in depth. The current preclinical and clinical evidence support two main considerations: (1) The microbiota might be a suitable source of novel diagnostic and prognostic LC biomarkers and (2) The microbiota modulation can be a powerful therapeutic strategy to improve the efficacy of ICIs in LC patients. Overall, the microbiota populating the lungs and the intestine represent a novel valuable weapon against LC.
Triple-negative breast cancer (TNBC) is a highly lethal and aggressive subtype of breast cancer (BC). A unique molecular signature, lack of specific targets, and the hostile tumor microenvironment make TNBC less responsive to existing chemotherapeutics. Recent studies have extensively reported long non-coding RNAs (lncRNAs) as critical mediators of cellular and molecular mechanisms of BC development and metastasis. They regulate genes at transcrip-tional, post-transcriptional, and translational levels by targeting key molecules and signaling mechanisms. This review aims to present oncogenic lncRNAs as promising targets of BC therapy. It primarily updated the current knowledge of the biology, types, and biogenesis of lncRNAs. This study used a combination of cancer stem cells and BCs, lncRNAs and BC development, lncRNAs and BC metastasis, lncRNAs, and targeted therapeutics as key words to retrieve the literature from Scopus, Web of Science, PubMed, and Google Scholar from 2015-2021. This review includes studies on the expression, diagnostic and prognostic importance, clinical trials, meta-analysis regarding lncRNAs and BC and excludes all abstracts and conference proceedings. We also present the association of lncRNAs and cellular and molecular mechanisms of cancer and their functional roles in BC development. The molecular mechanisms of major oncogenic lncRNAs H19, HOTAIR, and MALAT1 in BC metastasis and their targeting strategies using plant-derived natural compounds, small-molecule drugs, and RNA interference molecules are summarized. This review provides novel ideas for the development of targeted therapeutics for anti-lncRNA therapy of BC.
Immunotherapy based on T cells has greatly developed over the years. However, tumor cells can evolve many tumor evasion mechanisms that render them refractory to T-cell effector activities. Tumor evasion strategies involving immunological mechanisms have been largely discussed; nonetheless, the hostile microenvironment generated by tumor masses must also be taken into account. Among these hostile conditions are nutrient deprivation, production of toxic metabolites, and hypoxia, all of which induce T cell dysfunction. This minireview provides a perspective of the tumor evasion mechanisms on T cells where both the metabolism and the microenvironment play a role.
The discovery of TP53, the gene that encodes tumor suppressor p53, over 40 years ago is a breakthrough for deciphering the molecular mechanism of the most fundamental biological events. p53 is critical in maintaining genome integrity, as well as normal cell growth and cell death. Upon exposure to cellular stress, p53 induces the transcription of its target genes and regulates highly diverse signaling pathways related with DNA damage repair, cell cycle arrest, senescence, and apoptosis. Recent studies further highlight the importance of p53, as it is also involved in other cellular processes including cell metabolism, angiogenesis, and cell stemness. Aberrant p53 activity and expression level is frequently found in all human cancers, and is closely related with tumor progression as well as poor prognosis. More than 50% of tumor patients have mutations in their TP53, whereas in those with wild-type TP53, aberrant expressions of its negative regulators lead to the suppression of its expression level. Thus, efforts have been made to restore functional p53, leading to the development of small molecules to reactivate wild-type p53 properties in tumors harboring mutant TP53, or to inhibit p53 negative regulators in tumors with wild-type TP53. Furthermore, immunotherapy targeting p53 has also emerged as a potential anti-tumor therapeutic strategy. Herein, we summarize recent advances of therapeutic strategies targeting p53 for anti-tumor treatment.
In recent years, the treatment of various cancers with immunotherapeutic strategies has revolutionized the classical treatments with chemotherapy or radiation. Such immunotherapeutic strategies are effective only in a subset of cancer patients who were unresponsive to conventional therapies and are not generalized to all cancer types. Several mechanisms have been reported that underlie the failure of the natural anti-tumor immunity or the administered immunotherapeutic agents in the treatment of cancer. Among these mechanisms is the pivotal role played by the immunosuppressive tumor microenvironment (TME). The TME is complex and consists of the stroma, blood vessels, and several cell types that have a direct relationship with the tumor as well as the tumor-relationship with the TME. Among the immunosuppressive cells in the TME are the tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), T regulatory cells (Tregs), and cancer-associated fibroblasts (CAFs). These cells altogether inhibit both innate and the adaptive anti-tumor immune responses. Noteworthy, TAMs represent > 50 % of all the infiltrating cells in the TME and their frequencies correlate with poor prognoses in many cancers. The depletion or inactivation of TAMs has been reported to restore, in large part, the anti-tumor immune response in several cancers. In this review, we discuss (i) the interrelationship between TAMs and cancer stem cells, (ii) the various mechanisms by which TAMs suppress the immune response [e.g., expression of inhibitory receptors and ligands, secretion of immunosuppressive cytokines, secretion of chemokines, secretion of arginase 1, secretion of IDO1 and expression of the triggering receptor expressed on myeloid cells (TREM)], and (iii) targeting TAMs for immunotherapy (e.g., depletion of TAMs, killing of TAMs, inhibition of TAM recruitment, reprogramming of TAMs, targeting Toll-like receptors, inhibition of PI3K gamma, HDAC inhibitors, and inhibition of specific miRNA activities, and targeting TREM and exosomes). In addition, we present bioinformatic analyses that demonstrated that (i) TAM infiltration into many cancers correlated with poor survival (ii) the TAM infiltration was associated with the clinical stages of the cancer and (iii) there is a strong correlation between the TAM infiltrates and various immunosuppressive gene products. Although many clinical studies are underway to inhibit the immunosuppressive functions of TAMs through a variety of mechanisms, by either targeting TAMs alone or in combination with other therapeutics, we present various perspectives that need to be considered for the successful translational application of TAMs targeting alone or in combination with other therapies in the clinic.
Glioblastoma (GBM) is a most frequent and incurable primary brain tumor in adults. Tumor cells create the highly heterogeneous tumor microenvironment (TME) consisting of neoplastic, stromal and immune cells. Lack of reliable markers prevented the identification of cell subtypes and functional phenotypes of immune cells present in the GBM TME. Single-cell technologies provide high-resolution insights into the cellular and functional heterogeneity of TME that previous approaches failed to capture. Single-cell RNA sequencing (scRNA-seq) and cytometry by time-of-flight (CyTOF) allow quantification of whole transcriptomes or > 30 proteins in individual cells. Single-cell omics revisited earlier assumptions and reveal diversity of myeloid and lymphoid infiltrates in gliomas. Sc-omics results uncovered the diversity of immune cells in malignant gliomas and different prevalence of immune cell populations in tumors with distinct genetic alterations. Occurrence of microglia and monocytes-derived macrophages differs in IDH-wt and IDH-mut gliomas influencing the accumulation and activation of T cells. Cytokines/chemokines released by immunomodulatory macrophages instigate the enrichment of regulatory T cells in TME of IDH-wt gliomas resulting in suppression of cytotoxic T cells. Across molecular glioblastoma subtypes, the mesenchymal (MES)-like state shows the increased accumulation of myeloid cells and T cells and worst survival. These studies disclosed discrete cell states and signaling pathways that promote tumor progression, influence patient survival or make tumors vulnerable to immunotherapy, which allows the rational design of oncoimmunotherapeutics. We assess recent attempts at targeting specific immune cell populations or enzymes in those populations to achieve anti-glioma effects or restore anti-tumor responses.
Anti-angiogenesis is the therapeutic strategy designed to disrupt the vascular supply and starve tumors of nutrients and oxygen. This is achieved mainly by blocking the vascular endothelial growth factor (VEGF) actions, as the VEGF signaling pathway is considered the main angiogenesis promoter and is active in the tumor microenvironment (TME) under hypoxic conditions. A total of 16 anti-angiogenic agents, including anti-VEGF antibodies, anti-VEGF receptor (VEGFR) antibodies, as well as VEGFR tyrosine kinase inhibitors (TKIs), have been approved for certain types of cancer. However, despite the mechanistic rationale that strongly supports the benefit of antiangiogenics to stop cancer progression, both in monotherapy or in combination with chemotherapy or targeted therapies, the antiangiogenics demonstrated limited clinical benefits for most patients with cancer. A recent hypothesis is that the "normalization" of the entire TME through a combination of antiangiogenics with immune therapies and/or inhibitors of tumor-associated stromal cells could present a potential synergistic anti-tumor effect. The TME imprinting converges in epigenetic modifications in endothelial cells that switch to tumor pro-angiogenic endothelial cells and continue to support the aggressiveness of tumor cells, including resistance to antiangiogenic therapies. The present review summarizes the current status of antiangiogenic strategies, the molecular mechanisms underlying their failure, and we discuss some alternative mechanisms targeting angiogenesis.
In cancer patients, immune cells are often functionally compromised due to the immunosuppressive features of the tumor microenvironment (TME) which contribute to the failures in cancer therapies. Clinical and experimental evidence indicates that developing tumors adapt to the immunological environment and create a local microenvironment that impairs immune function by inducing immune tolerance and invasion. In this context, microenvironmental hypoxia, which is an established hallmark of solid tumors, significantly contributes to tumor aggressiveness and therapy resistance through the induction of tumor plasticity/heterogeneity and, more importantly, through the differentiation and expansion of immune-suppressive stromal cells. We and others have provided evidence indicating that hypoxia also drives genomic instability in cancer cells and interferes with DNA damage response and repair suggesting that hypoxia could be a potential driver of tumor mutational burden. Here, we reviewed the current knowledge on how hypoxic stress in the TME impacts tumor angiogenesis, heterogeneity, plasticity, and immune resistance, with a special interest in tumor immunogenicity and hypoxia targeting. An integrated understanding of the complexity of the effect of hypoxia on the immune and microenvironmental components could lead to the identification of better adapted and more effective combinational strategies in cancer immunotherapy. Clearly, the discovery and validation of therapeutic targets derived from the hypoxic tumor microenvironment is of major importance and the identification of critical hypoxia-associated pathways could generate targets that are undeniably attractive for combined cancer immunotherapy approaches.
Lyme disease (LD) is a growing infectious disease. Assays that can detect active infection early are needed to allow appropriate antibiotic therapy to begin when there is the best chance for a cure. The most frequently used assays are those based on antibodies to Borrelia burgdorferi or its variants, the causative agent of LD. However, an antibody test at a single time point only measures exposure, not necessarily an active infection. In contrast, antibodies that are bound to a target antigen in a circulating immune complex form do indicate active infection. Here, we present data supporting the use of such assays in LD.
Kruppel-like factor 4 (KLF4) is a member of the KLF zinc-finger−containing transcription factor family. Reported experimental data have indicated that KLF4 is either an oncogene or tumor suppressor. Moreover, other observations have indicated the role of KLF4 in the regulation of apoptosis, proliferation, and differentiation of B cells and B-cell malignancies. Interestingly, in contrast to adult lymphomas and most solid tumors, we have shown that KLF4 is overexpressed in pediatric non-Hodgkin lymphoma (NHL) tumor tissues, and overexpression of this protein predicted unresponsiveness to cyclophosphamide, doxorubicin, vincristine, and prednisolone treatment. Furthermore, we have found that the transcription factor Ying Yang 1 (YY1) is overexpressed in B-NHL and correlated with the expression of KLF4. Accordingly, we suggest that coexpression of KLF4 and YY1 may result from the transcriptional regulation of KLF4 by YY1. Indeed, this hypothesis was tested in various experimental designs that used both cell lines and tumor tissues derived from patients. From these findings, it was depicted that KLF4 and YY1 are regulated by microRNA-7 and that the activation of KLF4 can suppresses the extrinsic apoptotic pathway by inhibiting activation and cleavage of caspases 7, 9, and 3. Therefore, the overexpression of KLF4 in lymphoma may be responsible, in part, for pathogenesis, malignancy, and drug resistance. We propose that both KLF4 and YY1 may be prognostic biomarkers in pediatric lymphoma. Furthermore, the clinical testing of inhibitors of KLF4 may be a promising novel treatment for lymphoma.
Mycobacterium tuberculosis (Mtb), as observed in other pathogenic bacteria, utilizes signal transduction pathways dependent on the protein phosphorylation−dephosphorylation events to regulate its own metabolic processes but also to modulate and surrogate its host (macrophage) signal transduction−dependent defenses. In this review, we focus on the dominant phosphorylation pathways found in Mtb that are already described at the levels of genes and proteins, as well as their catalytic activity. Many of the systems we describe are the focus of intensive medicinal chemistry approaches to identify strategies to combat tuberculosis, with a special emphasis that will be dedicated to two important phosphatases secreted by Mtb: PtpA and PtpB.
Genetic analyses of Treponema pallidum subsp. pallidum (TPA) reference strains and human clinical isolates have revealed that there are two genetically distinct groups of TPA strains, one group related to the reference strain TPA Nichols (Nichols-like strains) and the second to the TPA SS14 strain (SS14-like strains). In general, the diversification of syphilis-causing strains into SS14- and Nichols-like groups is consistent with geographical and population separation of syphilis-infected human societies, such as separation of American and European populations before the 15th century, and this isolation could explain the missing intermediates between the two groups of TPA strains. In addition, whereas SS14-like strains are predominant among contemporary worldwide clinical isolates, a predominance of Nichols-like strains among reference laboratory strains (isolated in the United States during the 1900s) was found. The possible reasons for these discrepancies are discussed, but the ultimate reasons of both the diversification of syphilis-causing strains into SS14- and Nichols-like groups as well as the contemporary worldwide predominance of SS14-like strains in the human population remain unknown.
Autophagy is a cell-autonomous lysosomal degradative pathway implicated in various functions of the immune system. One of its key roles is the capture of intracellular pathogens and their delivery to lysosomes for elimination. Numerous in vitro studies have demonstrated that autophagy activation leads to killing of Mycobacterium tuberculosis (MTB) by infected macrophages. In this review, we summarize the functions of autophagy in MTB infection, as well as the molecular mechanisms involved in its regulation by both host and pathogen factors. The recent advances in our understanding of the role of autophagy proteins in, in vivo, control of MTB are discussed as well as the potential use of autophagy-based therapy and vaccine in the fight against tuberculosis.
Mycobacterium tuberculosis (Mtb) is a very successful pathogen possessing a plethora of tactics uniquely tailored to undermine the key macrophage defense system for its own survival and multiplication. Completion of the Mtb genome revealed the presence of two unique, acid rich families of proteins called PE /PPE proteins. Owing to their high abundance and expansion in pathogenic mycobacterial species, their association with the ESAT-6 (ESX) secretion system and constituting 7% of the coding potential of the Mtb genome, they have a great potential to act as virulent factors during mycobacterial pathogenesis. Though initially speculated to play a role in antigenic variation, current assessment of the functions of PE/PPE proteins reveal important and diverse roles during mycobacterial infection. Macrophages are important sentinel cells that arbitrate innate as well as adaptive immune responses. Paradoxically, macrophage anti-mycobacterial immune responses are readily manipulated by Mtb to favor their intracellular survival. Insights into the alteration of macrophage signaling pathways by PE/PPE proteins would offer a better perspective to develop effective anti-TB immunotherapeutics and vaccines. In this review, I discuss the significance of the PE/PPE proteins in the modulation of macrophage effector responses.
The Kruppel-like factor 4 (KLF4) transcriptional factor functions as a tumor suppressor or oncogene in different human cancers. Ovarian cancer is one of the most aggressive malignancies in women. In this review, we discuss the role of KLF4 and the KLF4 regulatory network in ovarian cancer. KLF4 expression inhibits ovarian cancer cell proliferation, migration, invasion, and metastasis. KLF4 inhibits the epithelial-to-mesenchymal transition by directly binding to the promoter of E-cadherin in ovarian cancer cells. Moreover, KLF4 inhibits the cancer stem cell phenotype in ovarian cancer. KLF4 not only regulates microRNA expression but is also targeted by microRNAs. It is a potential biomarker for prognosis and drug targeting in ovarian cancer and may contribute to ovarian cancer metastasis and chemoresistance through a complex gene regulatory network.
Kruppel-like factor 4 (KLF4) is a zinc finger transcription factor that can regulate diverse cellular physiological functions such as cell growth, death, differentiation, and migration. Recent studies have suggested that KLF4 can act as either a suppressor or oncogene for different types of cancers, ranging from solid tumors to leukemia, by regulating target genes involved in tumor cell proliferation, survival, metastasis, invasiveness, and the constitution of the tumor microenvironment. In most cancer types, KLF4 has shown the ability to inhibit tumor progression, thus raising the possibility that it may be a novel target for multiple types of cancer, including T-cell acute lymphoblastic leukemia, which lacks targeted drugs in clinical practice. A better understanding of the role of KLF4 in tumorigenesis will facilitate the application of this potential molecular target for tumor therapy.
The Kruppel-like transcription factor 4 (KLF4) is a member of a large family of Kruppel-like transcription factors. KLF4 exerts many functions in both normal and cancerous tissues. In cancer, KLF4 has been reported to act either as an oncogene or tumor suppressor. It is also involved in the regulation of cancer stem cells and resistance to cytotoxic therapeutics. The expression of KLF4 messenger RNA (mRNA) in a variety of hematologic and solid malignancies has been analyzed by bioinformatics. In the majority of the studied cancers, the findings reveal that the high expression levels of KLF4 were associated with tumor progression and that KLF4 was thus acting as an oncogene. In a small number of cancers, the expression level of KLF4 was associated with tumor regression and KLF4 was therefore acting as a tumor suppressor. The data analyzed herein by bioinformatics extended the findings reported in the literature for a few cancers and assigned KLF4 as either an oncogene or tumor suppressor for all cancers studied. The findings derived from bioinformatics require experimental validation. Hence, the expression level of KLF4 may be of prognostic significance for certain cancers, and furthermore, targeting KLF4 may be a potential therapeutic when it acts as an oncogene. We suggest the application of inhibitors specific for KLF4, alone or in combination with conventional therapies, in clinical trials for the reversal of resistance and for tumor suppression.
