Advances in cancer biology - metastasis最新文献

Background

Tumor-associated macrophages (TAMs) express cytokines and chemokines that can suppress antitumor immunity and promote tumor progression. The immunomodulatory and antitumor function of β-defensin 2 is still unclear, despite the evidence of infection response. We previously reported that β-defensin 2 modulates immunomodulatory and their antitumor function of macrophages in breast cancer. We investigate the association between β-defensin 2 and TAMs and determined the role in tumor-promoting attributes of TAMs reversal of phenotype in tumor regression.

Methods

Swiss albino mice and C127i breast cancer cell line was used in this study. C127i conditioned media was prepared and generated macrophage-derived TAMs to study antitumor function. Flow cytometry was performed for phenotype identification of macrophages and TAMs. MTT assay was performed to estimate cytotoxicity and dose optimization of β-defensin 2. Oxidative stress was analyzed by H₂O₂ and NO estimation, and qPCR was performed for iNOS, cytokines and chemokines expression.

Results

PEC harvested macrophages were characterized by flow-cytometry using F4/80, CD11c antibodies with 98% pure population of macrophages and cultured in C127i conditioned media for 7 days. TAMs markers were estimated, and it was found that 98% expression of F4/80, CD-206, and CD-115 expression compared to macrophages. Purified 100 ng/ml of β-defensin 2 was used to stimulate the TAMs population was viable, which was confirmed by cell viability assay. ROS levels decreased in TAMs treated with β-defensin 2 compared to control group. Interleukins (ILs)-6, 10, and 3, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β and chemokine ligand (CXCL)-1, 5 and 15, chemokine ligand (CCL)-24 and 5 decreased drastically compared to control.

Conclusion

This is the first report of β-defensin 2 on TAMs to elucidate the immunomodulatory and anti-tumor function. It was found that the cytokines, chemokines, and reactive oxygen species (ROS) expression pliably changed which facilitates tumor regression. β-defensin 2 must be targets as adjuvant for future cancer immunotherapeutic agent.

Mesothelin (MSLN), a tumor-associated antigen, is upregulated in various malignancies, including gastric cancer (GC). In addition, MSLN is found in the blood-stream of affected individuals, where it is referred to as soluble MSLN-related protein (SMRP). This study aims to investigate the role of MSLN in GC and evaluate its potential as a plasma biomarker for diagnosis and prognosis. Toward that end, GC tissues were obtained, upon signed consent, from affected individuals undergoing surgery or endoscopy (n = 82). Quantitative RT-PCR and immunohistochemistry were performed to determine MSLN expression. Simultaneously, The Cancer Genome Atlas (TCGA) database was mined to evaluate global status of MSLN gene expression in gastric cancer. Next, in vitro cell-culture studies were conducted to evaluate MSLN-driven proliferation properties. Using ELISA, sera from 55 GC-affected individuals were tested for MSLN level. Additionally, plasma mesothelin levels were compared in 6 cases before and after surgery. Upregulated MSLN expression was found in GC tissues, compared to adjacent normal tissues (p < 0.001). Cell culture studies with a MSLN-overexpressing stable GC line showed increased cell proliferation and invasion with ectopic MSLN. Additionally, gene-set-enrichment-analysis (GSEA) revealed an association of MSLN with the genes involved in the epithelial-mesenchymal transition and G2/M checkpoint. GC-affected cases showed higher serum MSLN levels, compared to healthy controls, with rapid decrease post-surgery. We found that MSLN upregulation correlates with poor clinical outcome and promotes growth advantage to GC cells in vitro. With further experimental evidences, we propose that MSLN could potentially be used as a plasma biomarker for diagnosis of GC.

The potential role for microRNA (miRNA) in the metastatic process that occurs in head and neck squamous cell carcinoma (HNSCC) was examined. miRNA was extracted from surgically excised tumor samples from 41 HNSCC cancer patients diagnosed with distant metastasis (DM) and from 53 patients who displayed no evidence of disease (NED) for a minimum of two years a minimum of two years after treatment with post-operative radiotherapy (PORT). A comparative two-way ANOVA of miRNA expression between DM and NED specimens identified 28 differentially expressed miRNAs with a false discovery rate (FDR) < 0.2 and fold change > 1.5. Two miRNA, miR-551a and miR-551b-3p, which share the same seed sequence, were associated with the DM group and with poor survival. Cell proliferation, migration, and invasion assays using the HN5 and UMSCC-17B HNSCC cell lines were performed after transfecting mimics or inhibitors of these miRNA uncovered an oncogenic role for miR-551a and miR-551b-3p. Furthermore, it was determined that miR-551a and miR-551b-3p directly target GLIPR2 mRNA, a negative regulator of autophagy. Overexpression of GLIPR2 reduced proliferation, migration and invasion of HNSCC cells. In addition, overexpression of miR-551a and miR-551b-3p increased radioresistance while GLIPR2 overexpression increased the radiosensitivity of HNSCC cell lines. These results propose that the miR-551a, miR-551b-3p and GLIPR2 axis plays an important role in tumor growth, invasion and metastasis, at least in part by modulating autophagy and that the proliferative and pro-survival roles of miR-551a and miR-551b-3p may represent potential therapeutic targets by inhibiting autophagy through the regulation of GLIPR2 expression in HNSCC.

Breast Cancer arises to be the most diagnosed cancer type in recent decades. It ranks to be the most vulnerable among women in terms of incidence and mortality. In 2020, 2.3 million women were diagnosed with breast cancer, and 6.85 lacs of death were reported globally. Here, we will focus mainly on TNBC, the most complicated breast cancer subtype. Therefore, novel treatment modalities are urgently required. Treatments like chemotherapy and radiotherapy limit the efficacy of therapeutic outcomes. Thus, new specific ideas are coming up to find a way out. For triple-negative breast cancer (TNBC), which is currently the most complex and challenging breast cancer subtype to treat, chemotherapy is still the standard of care. There has been a lot of study into novel treatments for people with TNBC because of its poor prognosis and the high chance of clinical recurrence. Chimeric antigen receptor (CAR) T cell-based immunotherapy directs the patient's immune system to recognize and eradicate tumor cells that express tumor-associated antigens (TAAs). It opens up a new area of research. Chimeric Antigen Receptor (CAR-T) cell therapy is an immunotherapy type derived from adoptive T cell relocation. CAR-T cells are well equipped with specific antibodies to identify antigens in self-tumor cells, thus bringing out cytotoxic outcomes. CARs are the modified receptors with improved specificity and responsiveness to intensify the recognition of cancer cells. The therapeutic effects of CAR-T cell treatment, including breast cancer, have not lived up to expectations in solid tumors despite recent triumphs in treating hematologic malignancies. In this review, we will discuss some recent developments in the field of breast cancer-specific immunotherapy using CAR-T.

High grade serous ovarian carcinoma (HGSOC) is a systemic malignancy characterized by metastatic lesions that spread within the peritoneal cavity. Despite initial sensibility to platinum-based chemotherapy, more than 80% of patients experience a relapse and acquire chemoresistance. From a genomic point of view, HGSOC shows a high level of inter- and intra-tumor heterogeneity. A better understanding of molecular mechanisms of this disease and the identification of driving genetic alterations could provide relevant indications for diagnostic and prognostic evaluation. Here, we accomplished a double-tier omic-analysis by integrating copy number variation data with matched gene expression profiling of multiple lesions in a cohort of 7 patients. We identified potential driver genes contained in amplified regions whose behavior seem to impact on gene expression program. They represent a distinctive signature that can segregate biopsies of different patients. Moreover, a further analysis highlighted ZNF696, ASPSCR1 and RHPN1 as key drivers, whose regulatory program is confirmed in TCGA cohort. In conclusion, exploration of gene expression program in HSGOC by integrating copy number and transcriptomic data from spatially separated samples obtained from seven patients led to the identification of genes whose amplification is significantly correlated to specific gene expression modules and are related to survival.

A potential treatment approach to treat this terminal illness is the mushroom-based lectin carrier system. It has been hypothesized that lectin-induced apoptotic nature causes necrosis, which leads to cell death, in cancer cells. The antibacterial and free radical scavenging capabilities of lectins were examined, according to the findings of our earlier lectin purification research. The goal of the current investigation is to determine whether Pleurotus flabellatus lectin (PFL-L) has any anti-cancer activity against colorectal cancer (HT29) and lung cancer (A549) cell lines. According to the findings of an in vitro cell line investigation, pre-treatment of the HT29 and A549 cell lines with PFL-L (10–100 μg/ml) significantly reduced the induction of apoptosis with an IC₅₀ range of PFL-L (67 & 60 μg/ml). PFL-L protects cells against cancer cells, according to a confocal microscope viability examination of A549 and HT29 cells, and a comet test was used to track induced apoptosis. Our findings imply that PFL-L has promising anti-cancer activity and targets several apoptotic-related processes present in the A549 and HT29 cells. Additionally, when compared to the control, PFL-L increased DNA damage and the potential loss of cancer cells. A549 and HT29 cells also showed signs of the increased apoptosis-related proteins Bcl-Xl, Bcl-2, Procaspase-3, Procaspase-9, MMP-3, MMP-9, B6, N-Cadherin, and E-Cadherin. Western blot examination revealed decreased expression of apoptosis-related proteins. The results of this study demonstrate that PFL-L has anti-cancer properties against induced apoptosis in an in vitro model of A549 and HT29 cells.

Metastatic cancer is responsible for the overwhelming majority of cancer-related deaths, with metastatic tumors being the most common neoplasms affecting the central nervous system. One of the major factors regulating tumor biology is the tumor microenvironment. However, little is known about the cellular and non-cellular composition of metastatic brain tumors and how tumor cell ontogeny influences the metastatic brain tumor microenvironment. By integrating multiplex immunohistochemistry and histopathological analysis to investigate composition and the spatial relationship between neoplastic cells, infiltrating and brain resident immune cells and the extracellular matrix, we demonstrate that metastatic brain tumors exhibit differences in extracellular matrix deposition, compared with the most common primary brain tumor type, glioblastoma, and that the dominant immune cell types in metastatic brain tumors are immunosuppressive macrophages, which preferentially localize to extracellular matrix-rich stromal regions.

Breast cancer (BC) is one of the most frequently diagnosed cancers in women worldwide. It has surpassed lung cancer as the leading cause of cancer-related death. Breast cancer brain metastasis (BCBM) is becoming a major clinical concern that is commonly associated with ER-ve and HER2+ve subtypes of BC patients. Metastatic lesions in the brain originate when the cancer cells detach from a primary breast tumor and establish metastatic lesions and infiltrate near and distant organs via systemic blood circulation by traversing the BBB. The colonization of BC cells in the brain involves a complex interplay in the tumor microenvironment (TME), metastatic cells, and brain cells like endothelial cells, microglia, and astrocytes. BCBM is a significant cause of morbidity and mortality and presents a challenge to developing successful cancer therapy. In this review, we discuss the molecular mechanism of BCBM and novel therapeutic strategies for patients with brain metastatic BC.

Nuclear medicine imaging of neuroendocrine neoplasm (NEN) patients could evidence cancer cell states related to glycolytic hypermetabolism, somatostatin (SST) receptors overexpression or norepinephrine (NE) transport system hyperactivity status of cancer cells profiles, according to the radiolabelled molecular probe used: fluorodeoxyglucose (FDG), octreotide (SST analogue) or the compound metaiodobenzylguanidine (NE analogue), respectively. NEN lesions with positive positron emission tomography with ¹⁸FDG (glucose analogue radiolabelled with fluoride-18) stablished a relationship with tumour aggressiveness and poorly differentiated cell morphology. Otherwise, NEN lesions evidencing somatostatin receptors (SSTR) overexpression or abnormal surface NE transporter system hyperactivity status of cancer cell profiles correlated with well differentiated cell morphology. Theoretically, the apparent correspondence between the triple-positive imaging of glycolytic hypermetabolism, SSTR overexpression and abnormal NE transporter system hyperactivity of overlapping cancer cell states in metastatic site of a NEN patient could be revealing a single tumorigenic subpopulation with a dynamic divergent differentiation potential. The complex events of metastasis progression included transdifferentiation from epithelial-to-mesenchymal to leave the primary neoplastic niche, probable as a collective migration of cancer cells, including cancer stem cells (CSCs), to circulating and reversibly transdifferentiating from mesenchymal-to-epithelial to settle in distant niches. Considering future research perspectives, we argued whether the apparent triple-positive matched correlative imaging with the radiolabelled molecular probes (glucose, SST and NE analogues) in patients’ metastatic niches could indicate potential biopsy sites to further investigation for the potential CSCs properties. We suggested that early treatment planning with lutetium-177-based peptide receptor radionuclide therapy, could provide for the blocking of poorly differentiated cell states at the point of differentiation to well differentiated cell states, and vice versa. In addition, specific individual cases should be considered for targeted-based therapy with radiolabelled-NE analogue, blocking dedifferentiation and transdifferentiation from abnormal NE transporter system hyperactivity status to SSTR overexpression cancer cell profile.

The ketogenic diet (KD) is a low-carbohydrate, high-fat diet that is primarily used to treat childhood epilepsy. The processes through which the ketogenic diet works, on the other hand, have been proposed as a preventative method for oxidative stress and as adjuvant therapy for various disorders, including cancer. The current review aim is to assess the effect of the ketogenic diet on oxidative stress and cancer. A review of the scientific literature on the effects of the ketogenic diet on oxidative stress, cancer, and the mitochondrial metabolism is provided. Furthermore, the review depicts the human research that evaluated the anti-tumour benefits of ketogenic diets on patients with cancer, with a total of 154 subjects. Although preclinical research indicates that KD has anticancer benefits, prolongs longevity, and inhibits cancer growth, human clinical trials are inconclusive. The effects of KD on cancer and as an adjuvant treatment are mostly unclear due to a paucity of high-quality clinical research. We suggest a series of research recommendations for clinical trials exploring the impact of KD on cancer growth and progression.