Targeting oral tumor microenvironment for effective therapy.

Oral cancers are among the common head and neck malignancies. Different anticancer therapy modalities such as chemotherapy, immunotherapy, radiation therapy, and also targeted molecular therapy may be prescribed for targeting oral malignancies. Traditionally, it has been assumed that targeting malignant cells alone by anticancer modalities such as chemotherapy and radiotherapy suppresses tumor growth. In the last decade, a large number of experiments have confirmed the pivotal role of other cells and secreted molecules in the tumor microenvironment (TME) on tumor progression. Extracellular matrix and immunosuppressive cells such as tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs) play key roles in the progression of tumors like oral cancers and resistance to therapy. On the other hand, infiltrated CD4 + and CD8 + T lymphocytes, and natural killer (NK) cells are key anti-tumor cells that suppress the proliferation of malignant cells. Modulation of extracellular matrix and immunosuppressive cells, and also stimulation of anticancer immunity have been suggested to treat oral malignancies more effectively. Furthermore, the administration of some adjuvants or combination therapy modalities may suppress oral malignancies more effectively. In this review, we discuss various interactions between oral cancer cells and TME. Furthermore, we also review the basic mechanisms within oral TME that may cause resistance to therapy. Potential targets and approaches for overcoming the resistance of oral cancers to various anticancer modalities will also be reviewed. The findings for targeting cells and potential therapeutic targets in clinical studies will also be reviewed.

A systematic review of the protective effects of silymarin/silibinin against doxorubicin-induced cardiotoxicity.

PURPOSE: Although doxorubicin chemotherapy is commonly applied for treating different malignant tumors, cardiotoxicity induced by this chemotherapeutic agent restricts its clinical use. The use of silymarin/silibinin may mitigate the doxorubicin-induced cardiac adverse effects. For this aim, the potential cardioprotective effects of silymarin/silibinin against the doxorubicin-induced cardiotoxicity were systematically reviewed. METHODS: In this study, we performed a systematic search in accordance with PRISMA guideline for identifying all relevant studies on "the role of silymarin/silibinin against doxorubicin-induced cardiotoxicity" in different electronic databases up to June 2022. Sixty-one articles were obtained and screened based on the predefined inclusion and exclusion criteria. Thirteen eligible papers were finally included in this review. RESULTS: According to the echocardiographic and electrocardiographic findings, the doxorubicin-treated groups presented a significant reduction in ejection fraction, tissue Doppler peak mitral annulus systolic velocity, and fractional shortening as well as bradycardia, prolongation of QT and QRS interval. However, these echocardiographic abnormalities were obviously improved in the silymarin plus doxorubicin groups. As well, the doxorubicin administration led to induce histopathological and biochemical changes in the cardiac cells/tissue; in contrast, the silymarin/silibinin co-administration could mitigate these induced alterations (for most of the cases). CONCLUSION: According to the findings, it was found that the co-administration of silymarin/silibinin alleviates the doxorubicin-induced cardiac adverse effects. Silymarin/silibinin exerts its cardioprotective effects via antioxidant, anti-inflammatory, anti-apoptotic activities, and other mechanisms.

Tumor microenvironment remodeling in oral cancer: Application of plant derived-natural products and nanomaterials.

Oral cancers consist of squamous cell carcinoma (SCC) and other malignancies in the mouth with varying degrees of invasion and differentiation. For many years, different modalities such as surgery, radiation therapy, and classical chemotherapy drugs have been used to control the growth of oral tumors. Nowadays, studies have confirmed the remarkable effects of the tumor microenvironment (TME) on the development, invasion, and therapeutic resistance of tumors like oral cancers. Therefore, several studies have been conducted to modulate the TME in various types of tumors in favor of cancer suppression. Natural products are intriguing agents for targeting cancers and TME. Flavonoids, non-flavonoid herbal-derived molecules, and other natural products have shown promising effects on cancers and TME. These agents, such as curcumin, resveratrol, melatonin, quercetin and naringinin have demonstrated potency in suppressing oral cancers. In this paper, we will review and discuss about the potential efficacy of natural adjuvants on oral cancer cells. Furthermore, we will review the possible therapeutic effects of these agents on the TME and oral cancer cells. Moreover, the potential of nanoparticles-loaded natural products for targeting oral cancers and TME will be reviewed. The potentials, gaps, and future perspectives for targeting TME by nanoparticles-loaded natural products will also be discussed.

A systematic review of the therapeutic effects of resveratrol in combination with 5-fluorouracil during colorectal cancer treatment: with a special focus on the oxidant, apoptotic, and anti-inflammatory activities.

PURPOSE: 5-fluorouracil (5-FU), an effective chemotherapy drug, is commonly applied for colorectal cancer treatment. Nevertheless, its toxicity to normal tissues and the development of tumor resistance are the main obstacles to successful cancer chemotherapy and hence, its clinical application is limited. The use of resveratrol can increase 5-FU-induced cytotoxicity and mitigate the unwanted adverse effects. This study aimed to review the potential therapeutic effects of resveratrol in combination with 5-FU against colorectal cancer. METHODS: According to the PRISMA guideline, a comprehensive systematic search was carried out for the identification of relevant literature in four electronic databases of PubMed, Web of Science, Embase, and Scopus up to May 2021 using a pre-defined set of keywords in their titles and abstracts. We screened 282 studies in accordance with our inclusion and exclusion criteria. Thirteen articles were finally included in this systematic review. RESULTS: The in vitro findings showed that proliferation inhibition of colorectal cancer cells in the groups treated by 5-FU was remarkably higher than the untreated groups and the co-administration of resveratrol remarkably increased cytotoxicity induced by 5-FU. The in vivo results demonstrated a decrease in tumor growth of mice treated by 5-FU than the untreated group and a dramatic decrease was observed following combined treatment of resveratrol and 5-FU. It was also found that 5-FU alone and combined with resveratrol could regulate the cell cycle profile of colorectal cancer cells. Moreover, this chemotherapeutic agent induced the biochemical and histopathological changes in the cancerous cells/tissues and these alterations were synergized by resveratrol co-administration (for most of the cases), except for the inflammatory mediators. CONCLUSION: The results obtained from this systematic review demonstrated that co-administration of resveratrol could sensitize the colorectal cancer cells to 5-FU treatment via various mechanisms, including regulation of cell cycle distribution, oxidant, apoptosis, anti-inflammatory effects.

Therapeutic potentials of resveratrol in combination with radiotherapy and chemotherapy during glioblastoma treatment: a mechanistic review.

Glioblastoma, WHO grade IV astrocytoma, is the most aggressive type of brain tumors. These cancerous cells have a rapid growth rate, tendency to penetrate vital brain structures, molecular heterogeneity, etc. and this cancer is associated with a poor prognosis and low survival rate. Due to the resistance of glioblastoma cells to conventional therapeutic modalities (such as radiation therapy and chemotherapy) as well as the adverse effects of these modalities, the researchers have attempted to discover an appropriate alternative or adjuvant treatment for glioblastoma. Resveratrol, as an herbal and natural polyphenolic compound, has anti-tumoral property and has shown to be effective in GBM treatment. Resveratrol exerts its anti-tumoral effect through various mechanisms such as regulation of cell cycle progression and cell proliferation, autophagy, oxidant system, apoptosis pathways, and so on. Resveratrol in combination with radiation therapy and chemotherapy has also been used. In the present study, we summarized the current findings on therapeutic potentials of resveratrol in glioblastoma radiotherapy and chemotherapy.

Targets for protection and mitigation of radiation injury.

Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in clinical and environmental radiobiology. Investigations in recent decades have suggested potential targets that are involved in the protection against radiation-induced damages to normal tissues and can be proposed for mitigation of radiation injury. Emerging evidences have been shown to be in contrast to an old dogma in radiation biology; a major amount of reactive oxygen species (ROS) production and cell toxicity occur during some hours to years after exposure to ionizing radiation. This can be attributed to upregulation of inflammatory and fibrosis mediators, epigenetic changes and disruption of the normal metabolism of oxygen. In the current review, we explain the cellular and molecular changes following exposure of normal tissues to ionizing radiation. Furthermore, we review potential targets that can be proposed for protection and mitigation of radiation toxicity.

Neuroprotective effect of melatonin on radiation-induced oxidative stress and apoptosis in the brainstem of rats.

This study aimed to determine the effects of melatonin on irradiation-induced apoptosis and oxidative stress in the brainstem region of Wistar rats. Therefore, the animals underwent whole-brain X-radiation with a single dose of 25 Gy in the presence or absence of melatonin pretreatment at a concentration of 100 mg/kg BW. The rats were allocated into four groups (10 rats in each group): namely, vehicle control (VC), 100 mg/kg of melatonin alone (MLT), irradiation-only (RAD), and irradiation plus 100 mg/kg of melatonin (RAM). An hour before irradiation, the animals received intraperitoneal (IP) melatonin and then were killed after 6 hr, followed by measurement of nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and total antioxidant capacity (TAC) in the brainstem region. Furthermore, the western blot analysis technique was performed to assess the caspase-3 expression level. Results showed significantly higher MDA and NO levels in the brainstem tissues for the RAD group when compared with the VC group (p < .001). Moreover, the irradiated rats exhibited a significant decrease in the levels of CAT, SOD, GPx, and TAC (p < .01, p < .001, p < .001, and p < .001, respectively) in comparison to the VC group. The results of apoptosis assessment revealed that the expression level of caspase-3 significantly rose in the RAD group in comparison with the VC group (p < .001). Pretreatment with melatonin ameliorated the radiation-induced adverse effects by decreasing the MDA and NO levels (p < .001) and increasing the antioxidant enzyme activities (p < .001). Consequently, the caspase-3 protein expression level in the RAM group showed a significant reduction in comparison with the RAD group (p < .001). In conclusion, melatonin approximately showed a capacity for neuroprotective activity in managing irradiation-induced oxidative stress and apoptosis in the brainstem of rats; however, the use of melatonin as a neuroprotective agent in humans requires further study, particularly clinical trials.

TGF-ß in radiotherapy: Mechanisms of tumor resistance and normal tissues injury.

Emerging evidences show that changes in tumor stroma can adapt cancer cells to radiotherapy, thereby leading to a reduction in tumor response to treatment. On the other hand, radiotherapy is associated with severe reactions in normal tissues which limit the amount radiation dose received by tumor. These challenges open a window in radiobiology and radiation oncology to explore mechanisms for improving tumor response and also alleviate side effects of radiotherapy. Transforming growth factor beta (TGF-ß) is a well-known and multitasking cytokine that regulates a wide range of reactions and interactions within tumor and normal tissues. Within tumor microenvironment (TME), TGF-ß is the most potent suppressor of immune system activity against cancer cells. This effect is mediated through stimulation of CD4+ which differentiates to T regulatory cells (Tregs), infiltration of fibroblasts and differentiation into cancer associated fibroblasts (CAFs), and also polarization of macrophages to M2 cells. These changes lead to suppression of cytotoxic CD8 + T lymphocytes (CTLs) and natural killer (NK) cells to kill cancer cells. TGF-ß also plays a key role in the angiogenesis, invasion and DNA damage responses (DDR) in cancer cells. In normal tissues, TGF-ß triggers the expression of a wide range of pro-oxidant and pro-fibrosis genes, leading to fibrosis, genomic instability and some other side effects. These properties of TGF-ß make it a potential target to preserve normal tissues and sensitize tumor via its inhibition. In the current review, we aim to explain the mechanisms of upregulation of TGF-ß and its consequences in both tumor and normal tissues.

A low-dose chest CT protocol for the diagnosis of COVID-19 pneumonia: a prospective study.

PURPOSE: The increasing trend of chest CT utilization during the COVID-19 pandemic necessitates novel protocols with reduced dose and maintained diagnostic accuracy. We aimed to investigate the diagnostic accuracy of 30-mAs chest CT protocol in comparison with a 150-mAs standard-dose routine protocol for imaging of COVID-19 pneumonia. METHODS: Upon IRB approval, consecutive laboratory-confirmed positive COVID-19 patients aged 50 years or older who were referred for chest CT scan and had same-day normal CXR were invited to participate in this prospective study. First, a standard-dose chest CT scan (150 mAs) was performed. Only if typical COVID-19 pneumonia features were identified, then a low-dose CT (30 mAs) was done immediately. Diagnostic accuracy of low-dose and standard-dose CT in the detection of typical COVID-19 pneumonia features were compared. RESULTS: Twenty patients with a mean age of 64.20 ± 13.8 were enrolled in the study. There was excellent intrareader agreement in detecting typical findings of COVID-19 pneumonia between low-dose and standard-dose (intraclass correlation coefficient [ICC] = 0.98-0.99, P values < 0.001 all readers). The mean effective dose values in standard- and low-dose groups were 6.60 ± 1.47 and 1.80 ± 0.42 mSv, respectively. Also, absolute cancer risk per mean cumulative effective dose values obtained from the standard- and low-dose CT examinations were 2.71 × 10-4 and 0.74 × 10-4, respectively. CONCLUSIONS: According to our study, it was found that proposed low-dose CT chest protocol is reliable in detecting COVID-19 pneumonia in daily practice with significant reduction in radiation dose and estimated cancer risk.

Dosimetric evaluation of PASSAG-U polymer gel dosimeter: Dependence of dose rate and photon energy.

OBJECTIVE: Several physical factors such as dose rate and photon energy may change response and sensitivity of polymer gel dosimeters. This study aims to evaluate the R2-dose response and sensitivity dependence of PASSAG-U gel dosimeters with 3% and 5% urea on dose rate and photon energy. MATERIALS AND METHODS: The PASSAG-U gel dosimeters were prepared under normal atmospheric conditions. The obtained gel dosimeters were irradiated to different dose rates (100, 200, and 300 cGy/min) and photon energies (6 and 15 MV). Finally, responses (R2) of the PASSAG-U gel dosimeters with 3% and 5% urea were analyzed by MRI technique at 1, 10, 14 days after the irradiation process. RESULTS: The findings showed that the R2-dose responses of PASSAG-U gel dosimeters with 3% and 5% urea do not vary under the differently evaluated dose rates and photon energies. The R2-dose sensitivity of PASSAG-U polymer gel dosimeter with 3% urea does not change under the differently evaluated dose rates and photon energies, but it changes for PASSAG-U polymer gel dosimeter with 5% urea. The dose resolution values ranged from 0.20 to 0.86 Gy and from 0.27 to 2.20 Gy for the PASSAG-U gel dosimeter with 3% and 5% urea for the different dose rates and photon energies, respectively. Furthermore, it was revealed that the R2-dose response and sensitivity dependence of PASSAG-U gel dosimeters with 3% and 5% urea on dose rate and photon energy can vary over post irradiation time. CONCLUSIONS: The study results demonstrated that dosimetric characteristics (dependence of dose rate and photon energy, and dose resolution) of PASSAG-U gel dosimeter with 3% were better than those of PASSAG-U gel dosimeter with 5% urea.

Contribution of regulatory T cells to cancer: A review.

Regulatory T cells (Tregs) represent a low number of T-cell population under normal conditions, and they play key roles for maintaining immune system in homeostasis. The number of these cells is extensively increased in nearly all cancers, which is for dampening responses from immune system against cancer cells, metastasis, tumor recurrence, and treatment resistance. The interesting point is that apoptotic Tregs are stronger than their live counterparts for suppressing responses from immune system. Tregs within the tumor microenvironment have extensive positive cross-talks with other immunosuppressive cells including cancer-associated fibroblasts, cancer cells, macrophage type 2 cells, and myeloid-derived suppressor cells, and they have negative interactions with immunostimulatory cells including cytotoxic T lymphocytes (CTL) and natural killer cells. A wide variety of markers are expressed in Tregs, among them forkhead box P3 (FOXP3) is the most specific marker and the master regulator of these cells. Multiple signals are activated by Tregs including transforming growth factor-ß, signal transducer and activator of transcription, and mTORC1. Treg reprogramming from an immunosuppressive to immunostimulatory proinflammatory phenotype is critical for increasing the efficacy of immunotherapy. This would be applicable through selective suppression of tumor-bearing receptors in Tregs, including FOXP3, programmed death-1, T-cell immunoglobulin mucin-3, and CTL-associated antigen-4, among others. Intratumoral Tregs can also be targeted by increasing the ratio for CTL/Treg.

Cancer stem cells (CSCs) in cancer progression and therapy.

Cancer stem cells (CSCs) are self-renewable cell types that are identified in most types of liquid and solid cancers and contributed to tumor onset, expansion, resistance, recurrence, and metastasis after therapy. CSCs are identified from the expression of cell surface markers, which is tumor-type dependent. The transition between CSCs with cancer cells and other non-CSCs occurs in cancers, which is possibly under the control of signals from CSCs and tumor microenvironment (TME), including CSC niche. Cancer-associated fibroblasts are among the most influential cells for promoting both differentiation of CSCs and dedifferentiation of non-CSCs toward attaining a CSC-like phenotype. WNT/ß-catenin, transforming growth factor-ß, Hedgehog, and Notch are important signals for maintaining self-renewal in CSCs. An effective therapeutic strategy relies on targeting both CSCs and non-CSCs to remove a possible chance of tumor relapse. There are multiple ways to target CSCs, including immunotherapy, hormone therapy, (mi)siRNA delivery, and gene knockout. Such approaches can be designed for suppressing CSC stemness, tumorigenic cues from TME, CSC extrinsic and/or intrinsic signaling, hypoxia or for promoting differentiation in the cells. Because of sharing a range of characteristics to normal stem/progenitor cells, CSCs must be targeted based on their unique markers and their preferential expression of antigens.

CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review.

CD8+ cytotoxic T lymphocytes (CTLs) are preferred immune cells for targeting cancer. During cancer progression, CTLs encounter dysfunction and exhaustion due to immunerelated tolerance and immunosuppression within the tumor microenvironment (TME), with all favor adaptive immune-resistance. Cancer-associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and regulatory T cells (Tregs) could make immunologic barriers against CD8 + T cell-mediated antitumor immune responses. Thus, CD8 + T cells are needed to be primed and activated toward effector CTLs in a process called tumor immunity cycle for making durable and efficient antitumor immune responses. The CD8 + T cell priming is directed essentially as a corroboration work between cells of innate immunity including dendritic cells (DCs) and natural killer (NK) cells with CD4 + T cells in adoptive immunity. Upon activation, effector CTLs infiltrate to the core or invading site of the tumor (so-called infiltrated-inflamed [I-I] TME) and take essential roles for killing cancer cells. Exogenous reactivation and/or priming of CD8 + T cells can be possible using rational immunotherapy strategies. The increase of the ratio for costimulatory to coinhibitory mediators using immune checkpoint blockade (ICB) approach. Programmed death-1 receptor (PD-1)-ligand (PD-L1) and CTL-associated antigen 4 (CTLA-4) are checkpoint receptors that can be targeted for relieving exhaustion of CD8 + T cells and renewing their priming, respectively, and thereby eliminating antigen-expressing cancer cells. Due to a diverse relation between CTLs with Tregs, the Treg activity could be dampened for increasing the number and rescuing the functional potential of CTLs to induce immunosensitivity of cancer cells.

Cyclooxygenase-2 in cancer: A review.

Cyclooxygenase-2 (COX-2) is frequently expressed in many types of cancers exerting a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and cancer cell resistance to chemo- and radiotherapy. COX-2 is released by cancer-associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the tumor microenvironment (TME). COX-2 induces cancer stem cell (CSC)-like activity, and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, invasion, and metastasis of cancer cells. COX-2 mediated hypoxia within the TME along with its positive interactions with YAP1 and antiapoptotic mediators are all in favor of cancer cell resistance to chemotherapeutic drugs. COX-2 exerts most of the functions through its metabolite prostaglandin E2. In some and limited situations, COX-2 may act as an antitumor enzyme. Multiple signals are contributed to the functions of COX-2 on cancer cells or its regulation. Members of mitogen-activated protein kinase (MAPK) family, epidermal growth factor receptor (EGFR), and nuclear factor-κß are main upstream modulators for COX-2 in cancer cells. COX-2 also has interactions with a number of hormones within the body. Inhibition of COX-2 provides a high possibility to exert therapeutic outcomes in cancer. Administration of COX-2 inhibitors in a preoperative setting could reduce the risk of metastasis in cancer patients. COX-2 inhibition also sensitizes cancer cells to treatments like radio- and chemotherapy. Chemotherapeutic agents adversely induce COX-2 activity. Therefore, choosing an appropriate chemotherapy drugs along with adjustment of the type and does for COX-2 inhibitors based on the type of cancer would be an effective adjuvant strategy for targeting cancer.

Transforming growth factor-ß signaling: Tumorigenesis and targeting for cancer therapy.

Transforming growth factor (TGF)-ß is a multitasking cytokine such that its aberrant expression is related to cancer progression and metastasis. TGF-ß is produced by a variety of cells within the tumor microenvironment (TME), and it is responsible for regulation of the activity of cells within this milieu. TGF-ß is a main inducer of epithelial-mesenchymal transition (EMT), immune evasion, and metastasis during cancer progression. TGF-ß exerts most of its functions by acting on TßRI and TßRII receptors in canonical (Smad-dependent) or noncanonical (Smad-independent) pathways. Members of mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B, and nuclear factor κß are involved in the non-Smad TGF-ß pathway. TGF-ß acts by complex signaling, and deletion in one of the effectors in this pathway may influence the outcome in a diverse way by taking even an antitumor role. The stage and the type of tumor (contextual cues from cancer cells and/or the TME) and the concentration of TGF-ß are other important factors determining the fate of cancer (progression or repression). There are a number of ways for targeting TGF-ß signaling in cancer, among them the special focus is on TßRII suppression.

NF-κB targeting for overcoming tumor resistance and normal tissues toxicity.

Radiotherapy and chemotherapy are two famous modalities in tumor-targeted therapy that lead to systemic and local toxicities for normal tissues. Moreover, several studies have confirmed that exposure of the tumor to radiation or chemotherapy drugs stimulate some signaling pathways in the tumor microenvironment (TME), leading to resistance of cancer cells to apoptosis, as well as promoting angiogenesis and tumor growth. Nuclear factor kappa B (NF-κB) plays a central role in the regulation of inflammatory responses in both normal tissues and tumors via the release of several cytokines, regulation of prostaglandins, reduction/oxidation (redox) reactions, angiogenesis, and cell death. Upregulation of NF-κB in normal tissues causes an appearance of inflammatory reactions and oxidative stress, whereas it regulates angiogenesis and suppresses apoptosis, leading to resistance to subsequent doses of radiation or chemotherapy. Selective inhibition of NF-κB in experimental studies has shown promising results for tumor sensitization via apoptosis induction, inhibition of angiogenesis, and increasing delay of tumor growth. The use of some agents for NF-κB inhibition has been shown to alleviate radiation/chemotherapy toxicities in normal cells/ tissues. In this current review, we explained the pivotal role of NF-κB in both normal tissue toxicity and tumor resistance. We also discussed the promising strategies for overcoming these problems with regard to chemotherapy and radiotherapy.

Melatonin and cancer: From the promotion of genomic stability to use in cancer treatment.

Cancer remains among the most challenging human diseases. Several lines of evidence suggest that carcinogenesis is a complex process that is initiated by DNA damage. Exposure to clastogenic agents such as heavy metals, ionizing radiation (IR), and chemotherapy drugs may cause chronic mutations in the genomic material, leading to a phenomenon named genomic instability. Evidence suggests that genomic instability is responsible for cancer incidence after exposure to carcinogenic agents, and increases the risk of secondary cancers following treatment with radiotherapy or chemotherapy. Melatonin as the main product of the pineal gland is a promising hormone for preventing cancer and improving cancer treatment. Melatonin can directly neutralize toxic free radicals more efficiently compared with other classical antioxidants. In addition, melatonin is able to regulate the reduction/oxidation (redox) system in stress conditions. Through regulation of mitochondrial nction and inhibition of pro-oxidant enzymes, melatonin suppresses chronic oxidative stress. Moreover, melatonin potently stimulates DNA damage responses that increase the tolerance of normal tissues to toxic effect of IR and may reduce the risk of genomic instability in patients who undergo radiotherapy. Through these mechanisms, melatonin attenuates several side effects of radiotherapy and chemotherapy. Interestingly, melatonin has shown some synergistic properties with IR and chemotherapy, which is distinct from classical antioxidants that are mainly used for the alleviation of adverse events of radiotherapy and chemotherapy. In this review, we describe the anticarcinogenic effects of melatonin and also its possible application in clinical oncology.

Fusobacterium nucleatum and colorectal cancer: A mechanistic overview.

Colorectal cancer (CRC) is the third most prevalent cancer in the world. There are many risk factors involved in CRC. According to recent findings, the tumor microenvironment and feces samples of patients with CRC are enriched by Fusobacterium nucleatum. Thus, F. nucleatum is proposed as one of the risk factors in the initiation and progression of CRC. The most important mechanisms of Fusobacterium nucleatum involved in CRC carcinogenesis are immune modulation (such as increasing myeloid-derived suppressor cells and inhibitory receptors of natural killer cells), virulence factors (such as FadA and Fap2), microRNAs (such as miR-21), and bacteria metabolism. The aim of this review was to evaluate the mechanisms underlying the action of F. nucleatum in CRC.

Regulation of tumor angiogenesis by microRNAs: State of the art.

MicroRNAs (miRNAs, miRs) are small (21-25 nucleotides) endogenous and noncoding RNAs involved in many cellular processes such as apoptosis, development, proliferation, and differentiation via binding to the 3'-untranslated region of the target mRNA and inhibiting its translation. Angiogenesis is a hallmark of cancer, which provides oxygen and nutrition for tumor growth while removing deposits and wastes from the tumor microenvironment. There are many angiogenesis stimulators, among which vascular endothelial growth factor (VEGF) is the most well known. VEGF has three tyrosine kinase receptors, which, following VEGF binding, initiate proliferation, invasion, migration, and angiogenesis of endothelial cells in the tumor environment. One of the tumor microenvironment conditions that induce angiogenesis through increasing VEGF and its receptors expression is hypoxia. Several miRNAs have been identified that affect different targets in the tumor angiogenesis pathway. Most of these miRNAs affect VEGF and its tyrosine kinase receptors expression downstream of the hypoxia-inducible Factor 1 (HIF-1). This review focuses on tumor angiogenesis regulation by miRNAs and the mechanism underlying this regulation.

Tumor microenvironment: Interactions and therapy.

Tumor microenvironment (TME) is a host for a complex network of heterogeneous stromal cells with overlapping or opposing functions depending on the dominant signals within this milieu. Reciprocal paracrine interactions between cancer cells with cells within the tumor stroma often reshape the TME in favor of the promotion of tumor. These complex interactions require more sophisticated approaches for cancer therapy, and, therefore, advancing knowledge about dominant drivers of cancer within the TME is critical for designing therapeutic schemes. This review will provide knowledge about TME architecture, multiple signaling, and cross communications between cells within this milieu, and its targeting for immunotherapy of cancer.