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Apoptosis is a programmed cell death that occurs naturally in physiological and pathological conditions. Defective apoptosis can trigger the development and progression of cancer. Experiments suggest the ability of secretome derived from mesenchymal stem cells (MSC) to induce apoptosis in cancer cells. We develop a hybrid discrete-continuous multiscale model to further investigate the effect of MSC-derived secretome in tumor growth. The model encompasses three biological scales. At the molecular scale, a system of ordinary differential equations regulate the expression of proteins involved in apoptosis signaling pathways. At the cellular scale, discrete equations control cellular migration, phenotypic switching, and proliferation. At the extracellular scale, a system of partial differential equations are employed to describe the dynamics of microenvironmental chemicals concentrations. The simulation is able to produce both avascular tumor growth rate and phenotypic patterns as observed in the experiments. In addition, we obtain good quantitative agreements with the experimental data on the apoptosis of HeLa cancer cells treated with MSC-derived secretome. We use this model to predict the growth of avascular tumor under various secretome concentrations over time.

BACKGROUND: Secreted factors contained in conditioned media (CM) of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) known as secretome, was suspected to have important roles in regulating cells. This study was conducted to investigate the role of CM-hUCB-MSCs-derived secretome in apoptosis and growth of HeLa cells.METHODS: HeLa cells were treated with secretome in various concentrations (0, 0.2, 2 and 20%) for 24 and 48 hours. Trypan blue exclusion assay was performed to detect cell viability. Meanwhile sub-G1 apoptotic assay was performed to detect apoptotic cells. The transition of mitochondrial transmembrane potential (TMP), which occurs in the apoptotic process, was analyzed by mitochondrial membrane potential (ΔΨM) assay. Both sub-G1 and ΔΨM assays were performed using FACSCanto flow cytometer. Statistical analyses were conducted using IBM SPSS Statistics to detect significance level at p<0.05.RESULTS: Secretome significantly induced cell death starting at concentration of 0.2% within a 24-hour period (p<0.05). Secretome significantly induced cell death in concentration and time dependent manner (p<0.05). The cell death was then confirmed as apoptosis through sub-G1 analysis. Due to the underlying apoptotic mechanism, we found distinct decrease of TMP, indicating an increase in mitochondrial membrane permeability of HeLa cells. In addition, we found that HeLa cell growth was inhibited partially by secretome.CONCLUSION: Taken together, we conclude that CMhUCB-MSCs-derived secretome significantly induced apoptosis of HeLa cells in a concentration and time dependent manner through mitochondrial apoptotic pathway. The secretome might also play important role in inhibiting HeLa cell growth.KEYWORDS: umbilical cord blood, mesenchymal stem cell, secretome, apoptosis, growth, cancer

Angiogenesis, a formation of blood vessels from an existing vasculature, plays a key role in tumor growth and its progression into cancer. The lining of blood vessels consists of endothelial cells (ECs) which proliferate and migrate, allowing the capillaries to sprout towards the tumor to deliver the needed oxygen. Various treatments aiming to suppress or even inhibit angiogenesis have been explored. Mesenchymal stem cells (MSCs) have recently been undergoing development in cell-based therapy for cancer due to their ability to migrate towards the capillaries and induce the apoptosis of the ECs, causing capillary degeneration. However, further investigations in this direction are needed as it is usually difficult to preclinically assess the efficacy of such therapy. We develop a hybrid multiscale model that integrates molecular, cellular, tissue and extracellular components of tumor system to investigate angiogenesis and tumor growth under MSC-mediated therapy. Our simulations produce angiogenesis and vascular tumor growth profiles as observed in the experiments. Furthermore, the simulations show that the effectiveness of MSCs in inducing EC apoptosis is density dependent and its full effect is reached within several days after MSCs application. Quantitative agreements with experimental data indicate the predictive potential of our model for evaluating the efficacy of cell-based therapies targeting angiogenesis.

Proliferating Cell Nuclear Antigen (PCNA) is one of the several markers of cellular proliferation. Epithelial proliferations play a significant role in the behaviour of odontogenic lesions. The objective of this study was to describe and compare the distribution of PCNA expression within the epithelial linings of odontogenic cysts. A total of 49 cases of odontogenic cysts consisting of 18 radicular cysts, 16 dentigerous cysts, 15 odontogenic keratocysts (OKCs) was studied. All tissues were processed routinely prior to embedding in paraffin. PCNA immunohistochemical staining was performed on 4 !-tm thick deparaffinized sections mounted on sialinized slides using the peroxidase antiperoxidase method. The distributions of PCNA expression in the cysts linings were noted and comparison was made qualitatively and quantitatively. PCNA labelling index was used for the quantitative assessment. The results showed that PCNA staining was distributed in the basal and supra basal cells for radicular cysts, dentigerous cysts, and OKCs. PCNA labelling index was highest in OKC (22.33±4.07). The high PCNA labelling index in OKC is indicative of high proliferative activity thus supporting previous reports of OKC as the most aggressive type of odontogenic cysts.

The epithelial cystic linings and adjacent connective tissues of 61 cases of odontogenic cysts (radicular cysts[RC], dentigerous cysts[DC] and odontogenic keratocysts[OKC]) and unicystic ameloblastomas(UA) were described and compared histopathologically. The type of epithelium in relation to the presence of rete processes and the distribution of chronic inflammatory cells were analyzed statistically. Significant associations between the presence of rete processes in the non-keratinized epithelial linings and inflammation in the subjacent connective tissues of RC and DC were found in this study. There was also a statistically significant association between the presence of rete Processes and nonkeratinized epithelial linings in OKC. The results also showed that in inflamed OKC, the cystic lining epithelium exhibited hyperplasia indistinguishable from lining epithelium of RC and DC. This study further showed that ameloblastomatous-like epithelial cystic linings were present in inflammed odontogenic cysts. All except for one case of unicystic ameloblastomas in this study showed ameloblastomatous epithelial cystic linings. It is recommended that the lining epithelium of RC and DC be examined carefully in order to rule out OKC. Similarly, ameloblastomatous-like lining epithelium arising from chronic inflammation in RC and DC should be differentiated from true ameloblastomatous cystic lining. Such careful examinations are diagnostically important in view of the similarities of epithelial cystic linings of inflamed OKC with DC and RC aggressive behavior ofOKC and UA.

Background: Nasopharyngeal carcinoma (NPC) is a malignant neoplasm arising from the mucosal epithelium of the nasopharynx with various cells differentiation. Nasopharyngeal carcinoma is vastly more common in certain regions of East Asia, South Asia and Africa with viral, dietary which is typically includes consumption of salted vegetables, fish, meat and genetic factors that implicated in its causation. The undifferentiated is the most common type of NPC and strongly associated with Epstein-Barr virus (EBV) infection. Purpose: This paper was aimed to review about molecular biomarker as non invasive diagnosis of NPC especially in related to

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