Does hysteroscopy promote tumor cell proliferation in endometrial cancer?

Peritoneal cytological investigation was carried out inpatients with endometrial cancer, who were subjected to hysteroscopy before the operation (37patients) or were operated on without hysteroscopy. Comparative analysis of the data didnt reveal the role of hysteroscopy in tumor cell dissemination.

Platelets, thrombo-inflammation and cancer

It has long been recognized a crucial role played by platelets in thrombosis and hemostasis. Along with that, laboratory and clinical data suggest that platelets contribute to tumor progression and metastasis through a variety of interactions with cancer cells. During oncological process, the platelet function becomes modulated via their activation and increased aggregation being one of the risk factors for developing thrombosis in cancer patients. The platelets per se enhance tumor cell dissemination, activate endothelial cells, and attract immune cells to the primary and metastatic tumor sites. In this review, we summarize the current knowledge about the complex interactions between platelets and tumor cells, as well as cells of the microenvironment, and discuss the development of new antitumor agents aimed at various arms in platelet functioning.

Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/β-arr1 Axis

Transcoelomic spread of serous ovarian cancer (SOC) results from the cooperative interactions between cancer and host components. Tumor-derived factors might allow the conversion of mesothelial cells (MCs) into tumor-associated MCs, providing a favorable environment for SOC cell dissemination. However, factors and molecular mechanisms involved in this process are largely unexplored. Here we investigated the tumor-related endothelin-1 (ET-1) as an inducer of changes in MCs supporting SOC progression. Here, we report a significant production of ET-1 from MCs associated with the expression of its cognate receptors, ETA and ETB, along with the protein β-arrestin1. ET-1 triggers MC proliferation via β-arrestin1-dependent MAPK and NF-kB pathways and increases the release of cancer-related factors. The ETA/ETB receptor activation supports the genetic reprogramming of mesothelial-to-mesenchymal transition (MMT), with upregulation of mesenchymal markers, as fibronectin, α-SMA, N-cadherin and vimentin, NF-kB-dependent Snail transcriptional activity and downregulation of E-cadherin and ZO-1, allowing to enhanced MC migration and invasion, and SOC transmesothelial migration. These effects are impaired by either blockade of ETAR and ETBR or by β-arrestin1 silencing. Notably, in peritoneal metastases both ETAR and ETBR are co-expressed with MMT markers compared to normal control peritoneum. Collectively, our report shows that the ET-1 axis may contribute to the early stage of SOC progression by modulating MC pro-metastatic behaviour via MMT.

The roles of distinct Ca2+ signaling mediated by Piezo and inositol triphosphate receptor (IP3R) in the remodeling of E-cadherin during cell dissemination

Given the role of E-cadherin (E-cad) in holding epithelial cells together, the inverse relationship between E-cad levels and cell invasion has been perceived as a principle underlying the invasiveness of tumor cells. In contrast, our study employing the Drosophila model of cell dissemination demonstrates that E-cad is necessary for the invasiveness of RasV12-transformed cells in vivo. Drosophila E-cad/β-catenin disassembles at adherens junctions and assembles at invasive protrusions—the actin- and cortactin-rich invadopodia-like protrusions associated with breach of the extracellular matrix (ECM)—during cell dissemination. Loss of E-cad attenuates dissemination of RasV12-transformed cells by impairing their ability to compromise the ECM. Strikingly, the remodeling of E-cad/β-catenin subcellular distribution is controlled by two discrete intracellular calcium signaling pathways: Ca2+ release from endoplasmic reticulum via the inositol triphosphate receptor (IP3R) disassembles E-cad at adherens junctions while Ca2+ entry via the mechanosensitive channel Piezo assembles E-cad at invasive protrusions. Thus, our study provides molecular insights into the unconventional role of E-cad in cell invasion during cell dissemination in vivo and describes the discrete roles of intracellular calcium signaling in the remodeling of E-cad/β-catenin subcellular localization.

Exosome-Mediated Crosstalk Between Tumor and Tumor-Associated Macrophages

Exosomes are nanosized vesicles, derived from the endolysosomal compartment of cells and can shuttle diverse biomolecules such as nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their origin cells. Delivery of these cargoes to recipient cells enables exosomes to influence diverse cellular functions. As one of the most abundant immune cells in the tumor microenvironment, tumor-associated macrophages (TAMs) are educated by the tumor milieu, which is rich in cancer cells and stroma components, to exert functions such as the promotion of tumor growth, immunosuppression, angiogenesis, and cancer cell dissemination. Herein, we focus on exosomes-mediated intercellular communication between tumor cells and TAM in the tumor microenvironment, which may provide new targets for anti-tumor treatment. In this review, we highlight the most recent studies on the effect of tumor/macrophage-derived exosomes on macrophage/tumor function in different cancer types.

Tumor Suppressor p53 Restrains Cancer Cell Dissemination by Modulating Mitochondrial Dynamics

Tumor suppressor p53 plays a central role in preventing tumorigenesis. Here, we unravel how p53 modulates mitochondrial dynamics to restrain the metastatic properties of cancer cells. p53 inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling to attenuate the protein level of mitochondrial fission process 1 (MTFP1), which fosters the pro-fission dynamin-related protein 1 (Drp1) phosphorylation. This regulatory mechanism allows p53 to restrict cell migration and invasion governed by Drp1-mediated mitochondrial fission. Downregulating p53 or elevating the molecular signature of mitochondrial fission correlates with aggressive tumor phenotypes and poor prognosis in cancer patients. Upon p53 loss, exaggerated mitochondrial fragmentation stimulates the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling resulting in epithelial-to-mesenchymal transition (EMT)-like changes in cell morphology, accompanied by accelerated matrix metalloproteinase-9 (MMP9) expression and invasive cell migration. Notably, blocking the p53 deficiency-induced activation of mTORC1/MTFP1/Drp1/ERK axis completely abolishes the morphological switch, MMP9 expression, and cancer cell dissemination. Our findings unveil a hitherto unrecognized molecular mechanism underlying the metastatic phenotypes of p53-compromised cancers.

Integrin β1 orchestrates the abnormal cell-matrix attachment and invasive behaviour of E-cadherin dysfunctional cells

Background Tumour progression relies on the ability of cancer cells to penetrate and invade neighbouring tissues. E-cadherin loss is associated with increased cell invasion in gastric carcinoma, and germline mutations of the E-cadherin gene are causative of hereditary diffuse gastric cancer. Although E-cadherin dysfunction impacts cell–cell adhesion, cell dissemination also requires an imbalance of adhesion to the extracellular matrix (ECM). Methods To identify ECM components and receptors relevant for adhesion of E-cadherin dysfunctional cells, we implemented a novel ECM microarray platform coupled with molecular interaction networks. The functional role of putative candidates was determined by combining micropattern traction microscopy, protein modulation and in vivo approaches, as well as transcriptomic data of 262 gastric carcinoma samples, retrieved from the cancer genome atlas (TCGA). Results Here, we show that E-cadherin mutations induce an abnormal interplay of cells with specific components of the ECM, which encompasses increased traction forces and Integrin β1 activation. Integrin β1 synergizes with E-cadherin dysfunction, promoting cell scattering and invasion. The significance of the E-cadherin-Integrin β1 crosstalk was validated in Drosophila models and found to be consistent with evidence from human gastric carcinomas, where increased tumour grade and poor survival are associated with low E-cadherin and high Integrin β1 levels. Conclusions Integrin β1 is a key mediator of invasion in carcinomas with E-cadherin impairment and should be regarded as a biomarker of poor prognosis in gastric cancer.

Platelet-Cancer Interplay: Molecular Mechanisms and New Therapeutic Avenues

Although platelets are critically involved in thrombosis and hemostasis, experimental and clinical evidence indicate that platelets promote tumor progression and metastasis through a wide range of physical and functional interactions between platelets and cancer cells. Thrombotic and thromboembolic events are frequent complications in patients with solid tumors. Hence, cancer modulates platelet function by directly inducing platelet-tumor aggregates and triggering platelet granule release and altering platelet turnover. Also, platelets enhance tumor cell dissemination by activating endothelial cell function and recruiting immune cells to primary and metastatic tumor sites. In this review, we summarize current knowledge on the complex interactions between platelets and tumor cells and the host microenvironment. We also critically discuss the potential of anti-platelet agents for cancer prevention and treatment.