Level Of Tumorigenicity Research Articles

Biological Evaluation of Triorganotin Derivatives as Potential Anticancer Agents.

Metal-derived platinum complexes are widely used to treat solid tumors. However, systemic toxicity and tumor resistance to these drugs encourage further research into similarly effective compounds. Among others, organotin compounds have been shown to inhibit cell growth and induce cell death and autophagy. Nevertheless, the impact of the ligand structure and mechanisms involved in the toxicity of organotin compounds have not been clarified. In the present study, the biological activities of commercially available bis(tributyltin) oxide and tributyltin chloride, in comparison to those of specially synthesized tributyltin trifluoroacetate (TBT-OCOCF3) and of cisplatin, were assessed using cells with different levels of tumorigenicity. The results show that tributyltins were more cytotoxic than cisplatin in all the tested cell lines. NMR revealed that this was not related to the interaction with DNA but to the inhibition of glucose uptake into the cells. Moreover, highly tumorigenic cells were less susceptible than nontumorigenic cells to the nonunique pattern of death induced by TBT-OCOCF3. Nevertheless, tumorigenic cells became sensitive when cotreated with wortmannin and TBT-OCOCF3, although no concomitant induction of autophagy by the compound was detected. Thus, TBT-OCOCF3 might be the prototype of a family of potential anticancer agents.

Rediscovering Potential Molecular Targets for Glioma Therapy Through the Analysis of the Cell of Origin, Microenvironment and Metabolism.

Gliomas are the most common type of malignant brain tumors. Despite significant medical advances, gliomas remain incurable and are associated with high mortality. Although numerous biomarkers of diagnostic value have been identified and significant progress in the prognosis of the outcome has been made, the treatment has not been parallelly improved during the last three decades. This review summarizes and discusses three aspects of recent discoveries related to glioma, with the objective to highlight the advantages of glioma-specific drugs targeting the cell of origin, microenvironment, and metabolism. Given the heterogeneous nature of gliomas, various cell populations have been implicated as likely sources of the tumor. Depending on the mutation(s) acquired by the cells, it is believed that neural stem/progenitor cells, oligodendrocyte progenitor cells, mature neurons, and glial cells can initiate cell transformation into a malignant phenotype. The level of tumorigenicity appears to be inversely correlated with the maturation of a given cell population. The microenvironment of gliomas includes non-cancer cells such as immune cells, fibroblasts, and cells of blood vessels, as well as secreted molecules and the extracellular matrix, and all these components play a vital role during tumor initiation and progression. We will discuss in detail how the tumor microenvironment can stimulate and drive the transformation of non-tumor cell populations into tumor-supporting cells or glioma cells. Metabolic reprogramming is a key feature of gliomas and is thought to reflect the adaptation to the increased nutritional requirements of tumor cell proliferation, growth, and survival. Mutations in the IDH gene can shape metabolic reprogramming and may generate some vulnerabilities in glioma cells, such as abnormal lipid metabolism and sensitivity to endoplasmic reticulum stress (ERS). We will analyze the prominent metabolic features of malignant gliomas and the key pathways regulating glioma metabolism. This review is intended to provide a conceptual background for the development of glioma therapies based on the properties of tumor cell populations, microenvironment, and metabolism.

Differential expression of CD44 and CD24 markers discriminates the epitheliod from the fibroblastoid subset in a sarcomatoid renal carcinoma cell line: evidence suggesting the existence of cancer stem cells in both subsets as studied with sorted cells

Epithelioid and fibroblastoid subsets coexist in the human sarcomatoid renal cell carcinoma (sRCC) cell line, RCC52, according to previous clonal studies. Herein, using monoclonal antibodies to CD44 and CD24 markers, we identified and isolated these two populations, and showed that CD44bright/CD24dim and CD44bright/CD24bright phenotypes correspond to epithelioid and fibroblastoid subsets, respectively. Both sorted subsets displayed different levels of tumorigenicity in xenotransplantation, indicating that each harbored its own cancer stem cells (CSCs). The CD44bright/CD24bright subset, associated with higher expression of MMP-7, -8 and TIMP-1 transcripts, showed greater migratory/invasive potential than the CD44bright/CD24dim subset, which was associated with higher expression of MMP-2, -9 and TIMP-2 transcripts. Both subsets differentially expressed stemness gene products c-Myc, Oct4A, Notch1, Notch2 and Notch3, and the RCC stem cell marker, CD105 in 4-5% of RCC52 cells. These results suggest the presence of CSCs in both sRCC subsets for the first time and should therefore be considered potential therapeutic targets for this aggressive malignancy.

Cancer stem cell targeting: are we there yet?

Several decades after the first notion that cancer cells are heterogeneous, not only histologically but also at the level of tumorigenicity, the existence of a tumor initiation population (so-called cancer stem cells) is now widely accepted. Here, we review the historical background leading up to the identification of this special cancer cell population and its role in the resistance of tumors to conventional therapies. In addition, we briefly review the clinical targeting strategy of the specific signaling network for cancer stem cells. Current clinical trials with newly developed drugs or older drugs for other uses are summarized to provide an understanding of the current status of strategies to target cancer stem cells.

Abstract 4366: miR-126 reduces the tumorigenicity of melanoma cells in vitro and alters the melanoma microenvironment

Abstract The microRNA (miRNA) miR-126 is highly expressed in endothelial cells and often reported as down-regulated in cancer. The present study thoroughly examines the functional relevance of miR-126 in melanoma progression and suggests a central role of this miRNA as prognostic marker and modulator of the melanoma microenvironment. Initially, the expression of miR-126 was quantified in two independent, isogenic cell line model series of melanoma progression. To further explore its functional role, two stable over-expression cell lines were generated and subjected to an extensive series of in vitro assays. Subsequently, the prognostic relevance of miR-126 was assessed via in situ hybridization on a large melanoma tissue microarray cohort. In both melanoma cell line systems, miR-126 expression was inversely correlated with the level of tumorigenicity. Over-expression of miR-126 in vitro resulted in a significant decrease in colony formation, both in the presence and absence of anchorage, while cell viability remained unaffected. Using a three-dimensional spheroid invasion assay, over-expression of miR-126 significantly reduced cell invasiveness. In addition, a substantial reduction in tumor cell adhesion to VCAM-1 coated micro-channels was observed when the adhesive capacity of miR-126 over-expressing cells was examined under shear stress using the Cellix's Microfluidic Platform. Using in situ hybridization on tissue microarrays containing melanoma tissue, miR-126 expression was evident in the tumor vasculature whereas melanoma cells did not appear to express miR-126. Analysis of the degree of vascular staining revealed a significant association between lower vascular miR-126 expression and lower T-stage. In addition, high vascular miR-126 scores were significantly associated with prolonged overall survival, in particular in high grade tumors (T-stages 3 and 4). Overall, miR-126 over-expression was shown to trigger a less aggressive phenotype in melanoma cells in vitro. Nonetheless, its clinical relevance in melanoma may primarily be mediated by the tumor vasculature. Depletion of miR-126 has previously been linked to a number of tumor relevant phenotypes, including inflammation. Vascular up-regulation of the miR-126 target protein VCAM-1 may mediate increased tumor infiltration of lymphocytes and macrophages, which are known to play a crucial role in tumor development and prognosis. This renders miR-126 an exciting target for closer investigation with regard to its role in the melanoma microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4366. doi:1538-7445.AM2012-4366

Tumor Induction in Mouse Liver: Di-isononyl Phthalate Acts via Peroxisome Proliferation

Recently several chronic toxicity/carcinogenicity studies of di-isononyl phthalate (DINP) have been reported. These studies defined effect levels for liver tumors in male and female F344 rats at dietary levels exceeding 700 mg/kg/day; the no effect levels were 359 mg/kg/day in males and 442 mg/kg/day in females. Similar results were found in male B6C3F1 mice, but in female mice a significant increase in liver tumors was found at 336 mg/kg/day, making 112 mg/kg/day the NOAEL for liver tumors in that sex and species. DINP induces peroxisomal proliferation, and that, along with evidence that DINP is not mutagenic, is presumptive evidence for peroxisomal proliferation as the underlying mode of action for liver tumor development. To further explore the relationship between peroxisome proliferation and tumor induction in male and female mice, indicators of peroxisomal proliferation including liver weight, peroxisomal volume density, induction of peroxisomal enzyme activity, enhanced replicative DNA synthesis, and rates of apoptosis were measured at all of the dietary levels used in the chronic study in mice (500, 1500, 4000, and 8000 ppm, or approximately 100, 300, 800, and 1600 mg/kg/day). Liver weights, peroxisomal volume, and peroxisomal enzyme activity were significantly elevated in both male and female mice at the tumorigenic levels. Cell proliferation was also elevated in male and female mice, although the increases at levels below 4000 ppm in female mice were not significantly different from control values. Apoptosis was elevated at the 4000 and 8000 ppm levels, paralleling the increases in liver weight. These data along with previous results satisfy the criteria of the International Agency for Research on Cancer (IARC) and demonstrate that peroxisomal proliferation was indeed the mode of action for DINP-induced liver tumor induction in mice.

Infection of five human liver cell lines by dengue-2 virus.

Elevated serum transaminase levels of dengue patients indicate the possible impact of dengue virus infection on liver function. To elucidate the action of dengue virus infection in liver cells, an in vitro cell line system was established that mimicked the liver status of diverse clinical patients. Briefly, four hepatoma cell lines (HA22T, Huh7, Hep3B, and PLC) and one nonmalignant hepatocyte cell line (Chang liver) were included, representing various levels of tumorigenicity and differentiation. Our data showed that in these five cell lines, dengue-2 virus attached to each cell type equally well; however, this virus had higher replication rates and levels of virion production in differentiated Huh7, PLC, Hep3B, and Chang liver cells. Likewise, a lower replication rate was observed in the de-differentiated HA22T cells. Differentiation-related factors seem to play an important role in dengue virus replication. Further study showed that sodium butyrate (NaB, a differentiation inducer) treatment enhanced dengue virus replication in HA22T cells. Moreover, we found that the severity of morphologic aberration and the increase in aspartate aminotransferase (AST) levels correlated with the virus replication rate in the four infected hepatoma cells. In conclusion, we showed that dengue virus can infect diverse liver cells with differing replication efficiency, which causes cytopathic effects (CPEs) of diverse severity. Among the CPEs, the increased AST levels correlated with the clinical results from 24 dengue fever patients, who showed increased AST levels at the onset of fever. In summary, we find that dengue-2 virus replicates actively and causes severe CPEs in differentiated hepatoma cells. Factors related to differentiation as well as tumorigenicity seem to play critical roles, though the mechanisms of action remain unclear.

Fibronectin, laminin in hybrids of Rous sarcoma virus transformed and normal mouse fibroblasts.

Hybrid clones derived from the fusion of normal and Rous sarcoma virus-transformed 3T3 fibroblasts were analyzed for fibronectin and laminin pattern of expression in order to find a possible correlation with tumorigenicity. Both organization in the pericellular matrix and secretion into the culture media were investigated by immunofluorescence and ELISA techniques. No significant difference in fibronectin or laminin release was found among hybrid clones exhibiting different levels of tumorigenicity. In contrast, distinctive immunofluorescence patterns of concomitant presence of low levels of fibronectin and high levels of laminin were constantly observed in all the tumorigenic clones.

Ia-like antigen expression on biologically different human melanoma cell lines

Ia-like antigen binding of a large panel of monoclonal antibodies (six anti-human Ia-like monoclonal antibodies and ten murine anti-Ia monoclonal antibodies cross-reactive with human Ia-like antigens) were compared on seven permanent human melanoma cell lines by radioimmunoassay. Cell lines were initiated from primary or metastatic tumors and presented various levels of tumorigenicity (assessed by heterotransplantation in nude mice) and pigmentation (shown by 5-S-cysteinyldopa determination and cytological data). Two cell lines originated from the same primary melanoma, while two other pairs of cell lines originated from superficial spreading melanoma or metastatic lymph node of the same patients. Identical Ia-like allodeterminants were found in cell lines of the same individual origin. Quantitative expression of β 2-microglobulin and Ia-like antigens was similar in all cell lines except for one, in which these molecules were expressed in lower amounts. These results indicate that Ia-like antigen expression of the cell lines is unrelated to primary or metastatic origin, degree of pigmentation and ability to grow in nude mice.