Morphological features of invasion of tumor cells of invasive ductal breast cancer

Background. Nowadays, it has been proven that along with the invasion of individual tumor cells, their group migration occurs in the invasive front of the tumor, and this is an important factor in tumor progression. Objective: to determine the features of tumor cell invasion in the invasive front (IF) of invasive ductal breast cancer (BCa) without special specific features (IC NST) and to establish associative links between them and the clinical and pathological characteristics of the disease. Methods. The study was performed on BCa samples (after hematoxylin and eosin stained) from 120 patients with invasive ductal BCa I-II stage with G2 grade of tumor differentiation that didn’t receive neoadjuvant chemotherapy. Results. Tumors were divided into 3 groups: with predominance of parenchymal component (PC), with the larger component of connective tissue, and relatively equivalent ratio of these components. Within the IF of the studied tumors of patients with ІІ stage of the tumor process, group invasion of tumor structures was mainly determined, both separately and in combination. In particular, an increase in solid structures in tumors with a predominance of the PC, and in neoplasms with expressed desmoplastic changes in connective tissue and their advantage, - alveolar, tubular, discrete. Conclusion. In tumors of patients with invasive ductal BCa in the invasive front is dominated by collective migration of tumor cells, which is the starting mechanism of tumor progression and the first step of the metastatic process. Defined associative links between the features of tumor cell invasion and the clinical and pathological characteristics of the tumor process in BCa patients can be used in predicting this form of cancer.

TAMI-24. INHIBITION OF GBM INVASION BY THE Α-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID (AMPA) GLUTAMATE RECEPTOR ANTAGONIST PERAMPANEL

BACKGROUND Extensive tumor cell invasion within the brain represents a major problem for effective treatment of glioblastomas (GBMs). The invasive processes can be divided into three types: Collective cell invasion, perivascular infiltration, and single-cell invasion into the brain parenchyma. GBM cells can form synapses with neural cells pointing at an extensive communication network between brain and GBM cells which can be mediated via the metabolites Glutamine and Glutamate both needed for GBM cell proliferation. In this context, it has been shown in preclinical models that Perampanel, an antiepileptic agent, functioning as non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, has an inhibitory effect on GBM growth. To delineate how Perampanel affects GBM invasion, we utilised a highly characterized 3D GBM-brain organoid invasion model where single-cell invasion was studied in real-time following Perampanel treatment. METHODS A brain coculture model, consisting of rat brain organoids expressing various markers of the human adult brain, where confronted with GFP-labelled tumor cells. By using time-lapse confocal microscopy, we quantified single-cell invasion patterns and speed of invasion using two glioma stem cell models (BG5 and BG7). RESULTS Perampanel treatment significantly reduces tumor cell invasion into the brain organoids with the strongest effect seen in the most invasive GBM (BG5). The single-tumor cell invasion ratio was reduced by 72 % compared to the control (p= 0.0033). In contrast, collective cell invasion was reduced by 19 % (p= 0.028). Statistical analysis was performed using an unpaired sample t-test. CONCLUSION The AMPA glutamate receptor antagonist Perampanel significantly inhibits GBM invasion, suggesting an important role of the glutamate-glutamine cycle between the GBM cells and neurons in the invasion process. Moreover, this communication and exchange of metabolites seem to be more prominent where single GBM cells invade into the brain parenchyma compared to areas where collective invasion take place.

Syndecans and Their Synstatins: Targeting an Organizer of Receptor Tyrosine Kinase Signaling at the Cell-Matrix Interface

Receptor tyrosine kinases (RTKs) and integrin matrix receptors have well-established roles in tumor cell proliferation, invasion and survival, often functioning in a coordinated fashion at sites of cell-matrix adhesion. Central to this coordination are syndecans, another class of matrix receptor, that organize RTKs and integrins into functional units, relying on docking motifs in the syndecan extracellular domains to capture and localize RTKs (e.g., EGFR, IGF-1R, VEGFR2, HER2) and integrins (e.g., αvβ3, αvβ5, α4β1, α3β1, α6β4) to sites of adhesion. Peptide mimetics of the docking motifs in the syndecans, called “synstatins”, prevent assembly of these receptor complexes, block their signaling activities and are highly effective against tumor cell invasion and survival and angiogenesis. This review describes our current understanding of these four syndecan-coupled mechanisms and their inhibitory synstatins (SSTNIGF1R, SSTNVEGFR2, SSTNVLA-4, SSTNEGFR and SSTNHER2).

Pathological Investigation of Meningioma Capsule with respect to Tumor Cell Invasion

OBJECTIVE No previous study has pathologically investigated whether the meningioma capsule presents with tumor cells. We investigated which types of tumor capsules include tumor cells to help decide the kind of capsules which can be left intraoperatively without recurrence risk. METHODS We investigated 22 specimens of 14 newly diagnosed meningiomas between February 2011 and June 2021. Capsules were classified into three types: tumor capsule (TC), capsule-like thickened arachnoid membrane (CAM), and extended membrane (EM). Capsule properties were scored as hardness (soft = 1, medium = 2, hard = 3) and transparency (high = 1, medium = 2, low = 3). Hardness, transparency, and score sum was compared between capsules with/without tumor invasion in CAM and EM types. RESULTS The mean follow-up duration was 28.1 months, and there was only one recurrence in a remote location from the residual capsule. Nine capsules were classified as TC, seven as CAM, and six as EM. 88.9% of TCs, 42.9% of CAMs, and 50% of EMs were invaded by tumor cells. Hardness, transparency, and score sum in CAM with tumor invasion was lower than in CAM without, but not significant (p = 0.114, p = 0.114, p = 0.057). CONCLUSION Thickened TC or soft and highly transparent CAM imply a high risk of tumor cell invasion, thus such cases should be followed up long and carefully. The hard and low transparent residual CAMs may have low risk of tumor invasion, thus these kinds of residual capsules might not increase the recurrence risk. Thus, leaving such capsules tightly adhered to the eloquent cortex is theoretically justified to avoid damaging the brain surface.

Tumor-Cell Invasion Initiates at Invasion Hotspots, an Epithelial Tissue-Intrinsic Microenvironment

Malignant cancers emerge in epithelial tissues through a progressive process in which a single transformed mutant cell becomes tumorigenic and invasive. Although numerous genes involved in the malignant transformation of cancer cells have been described, how tumor cells launch an invasion into the basal side of epithelial tissues remains elusive. Here, using a Drosophila wing imaginal disc epithelia, we show that genetically mosaic clones of cells mutant for a neoplastic-tumor-suppressor gene (nTSG) in combination with the oncogenic Ras (RasV12) expression initiate invasion into the basal side of the epithelial layer at specific spots in the epithelial tissue. In this "invasion hotspot", the oncogenic double-mutant cells activate c-Jun N-terminal kinase (JNK) signaling, which causes basal extrusion of the double-mutant cells and destruction of basement membrane through upregulation of a matrix metalloprotease, MMP1. Conversely, in other regions of the epithelial tissue, the double-mutant cells do not strongly activate JNK, deviate from the apical side of the epithelial layer, and show benign tumor growth in the lumen. These data indicate that the onset of tumor-cell invasion is highly dependent on the tissue-intrinsic local microenvironment. Given the conservation of genetic signaling pathways involved in this process, initiation of tumor-cell invasion from invasion hotspots in Drosophila wing imaginal epithelia could help us to understand the developmental mechanisms of invasive cancers.

Research Progress on the Antitumor Mechanism of Compound Kushen Injection

Compound Kushen Injection (CKI), as a clinical traditional Chinese medicine preparation, has prominent antitumor effect but with several side effects. A large number of studies have shown that CKI plays an antitumor role by regulating tumor cell proliferation, inducing tumor cell differentiation and apoptosis, inhibiting tumor cell invasion and metastasis, reducing tumor angiogenesis, regulating the immunity, and so on. Clinically, CKI is widely used to treat various tumors, where it is often combined with surgery, chemotherapy, radiotherapy, targeted therapy, and other antitumor treatments. This article reviews the antitumor mechanism of CKI and the progress of its clinical application in order to provide a theoretical basis for further clinical application.

OS06.6A Inhibition of GBM invasion by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist Perampanel

BACKGROUND Extensive tumor cell invasion within the brain represents a major problem for effective treatment of glioblastomas (GBMs). The invasive processes can be divided into three types: Collective cell invasion, perivascular infiltration and single-cell invasion into the brain parenchyma. It has recently been shown that GBM cells have the ability to form synapses with neural cells pointing at an extensive communication network between brain cells GBM cells. This communication network can be mediated via the metabolites glutamine and glutamate both needed for GBM cell proliferation. In this context, it has been shown in preclinical models that Perampanel, an antiepileptic agent, functioning as non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, has an inhibitory effect on GBM growth. In order to delineate how Perampanel affects GBM invasion, we here utilised a highly characterized 3D GBM-brain organoid invasion model where single-cell invasion was studied in real-time following Perampanel treatment. MATERIAL AND METHODS A brain coculture model, consisting of rat brain organoids expressing various markers of the human adult brain, where confronted with GFP-labelled tumor cells. By using time-lapse confocal microscopy, we quantified single-cell invasion patterns and speed of invasion using two glioma stem cell models (GSCs; BG5 and BG7). RESULTS Perampanel treatment significantly reduces tumor cell invasion into the brain organoids with the strongest effect seen in the most invasive GBM (BG5). Here, the single-tumor cell invasion ratio was reduced by 72 % compared to the control group (p=0.0033). In contrast, collective cell invasion was reduced by 19 % (p=0.028). Statistical analysis was performed using an unpaired sample t-test. CONCLUSION The AMPA glutamate receptor antagonist Perampanel significantly inhibits GBM invasion, suggesting an important role of the glutamate-glutamine cycle between the GBM cells and neurons in the invasion process. Moreover, this communication and exchange of metabolites seems to be more prominent where single GBM cells invade into the brain parenchyma compared to areas where collective invasion take place.

Characteristics of TIMP1, CD63, and β1-Integrin and the Functional Impact of Their Interaction in Cancer

Tissue Inhibitor of Metalloproteases 1, also known as TIMP-1, is named for its well-established function of inhibiting the proteolytic activity of matrix metalloproteases. Given this function, many studies were carried out to verify if TIMP-1 was able to interrupt processes such as tumor cell invasion and metastasis. In contrast, many studies have shown that TIMP-1 expression is increased in several types of tumors, and this increase was correlated with a poor prognosis and lower survival in cancer patients. Later, it was shown that TIMP-1 is also able to modulate cell behavior through the induction of signaling pathways involved in cell growth, proliferation, and survival. The mechanisms involved in the regulation of the pleiotropic functions of TIMP-1 are still poorly understood. Thus, this review aimed to present literature data that show its ability to form a membrane complex with CD63 and β1-integrin, and point to N-glycosylation as a potential regulatory mechanism of the functions exerted by TIMP-1. This article reviewed the characteristics and functions performed individually by TIMP1, CD63, and β1-integrin, the roles of the TIMP-1/CD63/β1-integrin complex, both in a physiological context and in cancer, and the regulatory mechanisms involved in its assembly.