Focal adhesion kinase (FAK) is an important mediator of extracellular matrix integrin signaling, cell motility, cell proliferation and cell survival. Increased FAK expression is observed in a variety ...of solid human tumors and increased FAK expression and activity frequently correlate with metastatic disease and poor prognosis. Herein we identify miR-7 as a direct regulator of FAK expression. miR-7 expression is decreased in malignant versus normal breast tissue and its expression correlates inversely with metastasis in human breast cancer patients. Forced expression of miR-7 produced increased E-CADHERIN and decreased FIBRONECTIN and VIMENTIN expression in breast cancer cells. The levels of miR-7 expression was positively correlated with E-CADHERIN mRNA and negatively correlated with VIMENTIN mRNA levels in breast cancer samples. Forced expression of miR-7 in aggressive breast cancer cell lines suppressed tumor cell monolayer proliferation, anchorage independent growth, three-dimensional growth in Matrigel, migration and invasion. Conversely, inhibition of miR-7 in the HBL-100 mammary epithelial cell line promoted cell proliferation and anchorage independent growth. Rescue of FAK expression reversed miR-7 suppression of migration and invasion. miR-7 also inhibited primary breast tumor development, local invasion and metastatic colonization of breast cancer xenografts. Thus, miR-7 expression is decreased in metastatic breast cancer, correlates with the level of epithelial differentiation of the tumor and inhibits metastatic progression.
Cancer cells display phenotypic equilibrium between the stem-like and differentiated states during neoplastic homeostasis. The functional and mechanistic implications of this subpopulation plasticity ...remain largely unknown. Herein, it is demonstrated that the breast cancer stem cell (BCSC) secretome autonomously compresses the stem cell population. Co-implantation with BCSCs decreases the tumor-initiating capacity yet increases metastasis of accompanying cancer cells, wherein DKK1 is identified as a pivotal factor secreted by BCSCs for such functions. DKK1-promotes differentiation is indispensable for disseminated tumor cell metastatic outgrowth. In contrast, DKK1 inhibitors substantially relieve the metastatic burden by restraining metastatic cells in the dormant state. DKK1 increases the expression of SLC7A11 to protect metastasizing cancer cells from lipid peroxidation and ferroptosis. Combined treatment with a ferroptosis inducer and a DKK1 inhibitor exhibits synergistic effects in diminishing metastasis. Hence, this study deciphers the contribution of CSC-regulated phenotypic plasticity in metastatic colonization and provides therapeutic approaches to limit metastatic outgrowth.
Mitochondria, well recognized as the “powerhouse” of cells, are maternally inherited organelles with bacterial ancestry that play essential roles in a myriad of cellular functions. It has become ...profoundly evident that mitochondria regulate a wide array of cellular and metabolic functions, including biosynthetic metabolism, cell signaling, redox homeostasis, and cell survival. Correspondingly, defects in normal mitochondrial functioning have been implicated in various human malignancies. Cancer development involves the activation of oncogenes, inactivation of tumor suppressor genes, and impairment of apoptotic programs in cells. Mitochondria have been recognized as the site of key metabolic switches for normal cells to acquire a malignant phenotype. This review outlines the role of mitochondria in human malignancies and highlights potential aspects of mitochondrial metabolism that could be targeted for therapeutic development.
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•The physiological role of mitochondria to maintain cellular processes.•Pathological conditions associated with mitochondrial dysfunction.•Targeting mitochondria-based strategies possess great potential in oncology.
Bcl-2 agonist of cell death (BAD) is a BH3-only member of the Bcl-2 family which possesses important regulatory function in apoptosis. BAD has also been shown to possess many non-apoptotic functions ...closely linked to cancer including regulation of glycolysis, autophagy, cell cycle progression and immune system development. Interestingly, BAD can be either pro-apoptotic or pro-survival depending on the phosphorylation state of three specific serine residues (human S75, S99 and S118). Expression of BAD and BAD phosphorylation patterns have been shown to influence tumor initiation and progression and play a predictive role in disease prognosis, drug response and chemosensitivity in various cancers. This review aims to summarize the current evidence on the functional role of BAD phosphorylation in human cancer and evaluate the potential utility of modulating BAD phosphorylation in cancer.
•BAD has pro-apoptosis and pro-survival functions involved in cancer development.•BAD is phosphorylated by kinases that are linked to cancer cell survival pathways.•Phosphorylation of BAD were shown to promote survival and drug resistance in cancer.•Abrogating BAD phosphorylation by kinase inhibitors have shown limited success.•Novel strategies to target BAD phosphorylation need to be developed.
•A comprehensive introduction on the characteristics of TNBC and its heterogeneity.•A comprehensive comparison of TNBC prevalence in Western and Asian countries is portrayed.•Risk factors that have ...been identified to contribute to the onset, disease progression and drug response of TNBC.•Current standard treatment for TNBC and on-going clinical trials in Asia are discussed.•Recent novel biomarkers with therapeutic values for TNBCs are highlighted.
While tremendous improvement has been made for the treatment of breast cancers, the treatment of triple negative breast cancer (TNBC) still remains a challenge due to its aggressive characteristics and limited treatment options. Most of the studies on TNBC were conducted in Western population and TNBC is reported to be more frequent in the African women. This review encapsulates the studies conducted on TNBC patients in Asian population and elucidates the similarities and differences between these two regions. The current treatment of TNBC includes surgery, radiotherapy and chemotherapy. In addition to the current chemotherapies, which mainly include cytotoxic agents, such as taxanes and anthracyclines, many clinical trials are investigating the potential use of other chemotherapy drugs, targeted therapeutics and combinational therapies to treat TNBC. Moreover, this review also integrates the studies involving novel markers, which will help us to dissect the pathologic process of TNBC and in turn facilitate the development of better treatment strategies to combat TNBC.
Precision medicine promises to better classify patients by individual clinical and biological biomarkers, which may provide an accurate assessment of disease risk, diagnosis, prognosis and treatment ...response. Cancer frequently displays substantial inter-tumor and intra-tumor heterogeneity and hence oncology is well suited for application of precision approaches. Recent studies have demonstrated that dysregulated lncRNAs play pivotal roles in tumor heterogeneity. In this review, attention is focused on the potential applications of lncRNAs as biomarker candidates for cancer risk evaluation, detection, surveillance and prognosis. LncRNAs are often stable in clinical samples and easily detected. The functional implications and therapeutic potential of targeting lncRNAs in human cancer are further discussed. Finally, existing deficiencies and future perspectives in translating fundamental lncRNA knowledge into clinical practice are highlighted.
•LncRNAs play pivotal roles in precision oncology.•LncRNAs contribute to cancer predisposition evaluation.•LncRNAs serve as biomarkers for cancer detection and prognosis.•Therapeutic potential of lncRNAs in targeted therapy and immunotherapy.
Emerging evidence indicates that the miR-23a/24-2/27a cluster may possess a causal role in mammary tumorigenesis and function as a novel class of oncogenes. However, the regulatory mechanism of the ...miR-23a/24-2/27a cluster in mammary carcinoma cell invasion and migration is still largely unknown. We observed that the expression levels of miR-23a, miR-24-2 and miR-27a were significantly higher in breast cancer with lymph node metastasis, compared with that from patients without lymph node metastasis or normal tissue. Forced expression of the miR-23a/24-2/27a cluster promoted mammary carcinoma cell migration, invasion, and hepatic metastasis, through targeting Sprouty2 (SPRY2) and consequent activation of p44/42 MAPK. Epidermal growth factor induced the expression of the transcription factor c-MYC, which promoted the expression of mature miR-23a, miR-24-2, and miR-27a and subsequently decreased expression of SPRY2 and activated p44/42 MAPK to promote mammary carcinoma cell migration and invasion. We therefore suggest a novel link between epidermal growth factor and the miR-23a/24-2/27a cluster via the regulation of c-MYC, providing the potential for the miR-23a/24-2/27a cluster to be used as biomarker in the diagnosis and/or treatment of breast cancer.
The regulation of the miR-23a/24-2/27a cluster is largely unknown.
EGF induced c-MYC expression to promote the expression of the miR-23a/24-2/27a cluster, resulting in decreased expression of Sprouty2 and increased activation of p44/42 MAPK to stimulate mammary carcinoma cell invasion and subsequent hepatic metastases.
EGF promoted mammary carcinoma cell invasion and hepatic metastasis.
The miR-23a/24-2/27a cluster might be used as a biomarker for breast cancer metastasis.
Anthropogenic carbon nanotubes, with a fibrous structure and physical properties similar to asbestos, have recently been found within human lung tissues. However, the reported ...carbon-nanotube-elicited pulmonary pathologies have been mostly confined to inflammatory or neoplastic lesions in the lungs or adjacent tissues. In the present study, we demonstrate that a single pulmonary exposure to multi-walled carbon nanotubes dramatically enhances angiogenesis and the invasiveness of orthotopically implanted mammary carcinoma, leading to metastasis and rapid colonization of the lungs and other organs. Exposure to multi-walled carbon nanotubes stimulates local and systemic inflammation, contributing to the formation of pre-metastatic and metastatic niches. Our study suggests that nanoscale-material-elicited pulmonary lesions may exert complex and extended influences on tumour progression. Given the increasing presence of carbon nanotubes in the environment, this report emphasizes the urgent need to escalate efforts assessing the long-term risks of airborne nanomaterial exposure in non-lung cancer progression.
The contemporary use of nanomedicines for cancer treatment has been largely limited to serving as carriers for existing therapeutic agents. Here, we provide definitive evidence that, the ...metallofullerenol nanomaterial Gd@C82(OH)22, while essentially not toxic to normal mammary epithelial cells, possesses intrinsic inhibitory activity against triple-negative breast cancer cells. Gd@C82(OH)22 blocks epithelial-to-mesenchymal transition with resultant efficient elimination of breast cancer stem cells (CSCs) resulting in abrogation of tumour initiation and metastasis. In normoxic conditions, Gd@C82(OH)22 mediates these effects by blocking TGF-β signalling. Moreover, under hypoxic conditions found in the tumour microenvironment, cellular uptake of Gd@C82(OH)22 is facilitated where it functions as a bi-potent inhibitor of HIF-1α and TGF-β activities, enhancing CSC elimination. These studies indicate that nanomaterials can be engineered to directly target CSCs. Thus, Gd-metallofullerenol is identified as a kind of non-toxic CSC specific inhibitors with significant therapeutic potential.
Transplantation of mesenchymal stem cells (MSCs) holds promise to repair severe traumatic injuries. However, current transplantation practices limit the potential of this technique, either by losing ...the viable MSCs or reducing the performance of resident MSCs. Herein, we design a "bead-jet" printer, specialized for high-throughput intra-operative formulation and printing of MSCs-laden Matrigel beads. We show that high-density encapsulation of MSCs in Matrigel beads is able to augment MSC function, increasing MSC proliferation, migration, and extracellular vesicle production, compared with low-density bead or high-density bulk encapsulation of the equivalent number of MSCs. We find that the high-density MSCs-laden beads in sparse patterns demonstrate significantly improved therapeutic performance, by regenerating skeletal muscles approaching native-like cell density with reduced fibrosis, and regenerating skin with hair follicle growth and increased dermis thickness. MSC proliferation within 1-week post-transplantation and differentiation at 3 - 4 weeks post-transplantation are suggested to contribute therapy augmentation. We expect this "bead-jet" printing system to strengthen the potential of MSC transplantation.
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