Nitric Oxide: The Missing Link in Omentum-Induced Metabolic reprogramming of ovarian cancers

A novel metabolic regulatory mechanism of ovarian cancer by omentum adipose-derived stroma cells (O-ASCs) has been discovered. O-ASCs induce survival, migration, and chemoresistance of ovarian cancer cells. However, the underpinning mechanism behind the metabolic modulation was not understood. Here, O-ASCs are shown to promote nitric oxide (NO) homeostasis in ovarian cancers by generating the pool of arginine. Ovarian cancer cells benefit from tumor microenvironment’s elements and expand their growth. In turn, cancer cells modify the elements’ fate to further take advantage of nutrients and resources. A unique combinatory drug treatment is proposed to target O-ASCs-induced chemoresistance of ovarian cancer cells

Human Omental-Derived Adipose Stem Cells Increase Ovarian Cancer Proliferation, Migration, and Chemoresistance

Objectives: Adipose tissue contains a population of multipotent adipose stem cells (ASCs) that form tumor stroma and can promote tumor progression. Given the high rate of ovarian cancer metastasis to the omental adipose, we hypothesized that omental-derived ASC may contribute to ovarian cancer growth and dissemination. Materials and Methods: We isolated ASCs from the omentum of three patients with ovarian cancer, with (O-ASC4, O-ASC5) and without (O-ASC1) omental metastasis. BM-MSCs, SQ-ASCs, O-ASCs were characterized with gene expression arrays and metabolic analysis. Stromal cells effects on ovarian cancer cells proliferation, chemoresistance and radiation resistance was evaluated using co-culture assays with luciferase-labeled human ovarian cancer cell lines. Transwell migration assays were performed with conditioned media from O-ASCs and control cell lines. SKOV3 cells were intraperitionally injected with or without O-ASC1 to track in-vivo engraftment. Results: O-ASCs significantly promoted in vitro proliferation, migration chemotherapy and radiation response of ovarian cancer cell lines. O-ASC4 had more marked effects on migration and chemotherapy response on OVCA 429 and OVCA 433 cells than O-ASC1. Analysis of microarray data revealed that O-ASC4 and O-ASC5 have similar gene expression profiles, in contrast to O-ASC1, which was more similar to BM-MSCs and subcutaneous ASCs in hierarchical clustering. Human O-ASCs were detected in the stroma of human ovarian cancer murine xenografts but not uninvolved ovaries. Conclusions: ASCs derived from the human omentum can promote ovarian cancer proliferation, migration, chemoresistance and radiation resistance in-vitro. Furthermore, clinical O-ASCs isolates demonstrate heterogenous effects on ovarian cancer in-vitro

Modeling of Patient-Derived Xenografts in Colorectal Cancer.

Developing realistic preclinical models using clinical samples that mirror complex tumor biology and behavior are vital to advancing cancer research. While cell line cultures have been helpful in generating preclinical data, the genetic divergence between these and corresponding primary tumors has limited clinical translation. Conversely, patient-derived xenografts (PDX) in colorectal cancer are highly representative of the genetic and phenotypic heterogeneity in the original tumor. Coupled with high-throughput analyses and bioinformatics, these PDXs represent robust preclinical tools for biomarkers, therapeutic target, and drug discovery. Successful PDX engraftment is hypothesized to be related to a series of anecdotal variables namely, tissue source, cancer stage, tumor grade, acquisition strategy, time to implantation, exposure to prior systemic therapy, and genomic heterogeneity of tumors. Although these factors at large can influence practices and patterns related to xenotransplantation, their relative significance in determining the success of establishing PDXs is uncertain. Accordingly, we systematically examined the predictive ability of these factors in establishing PDXs using 90 colorectal cancer patient specimens that were subcutaneously implanted into immunodeficient mice. Fifty (56%) PDXs were successfully established. Multivariate analyses showed tissue acquisition strategy [surgery 72.0% (95% confidence interval (CI): 58.2-82.6) vs. biopsy 35% (95% CI: 22.1%-50.6%)] to be the key determinant for successful PDX engraftment. These findings contrast with current empiricism in generating PDXs and can serve to simplify or liberalize PDX modeling protocols. Better understanding the relative impact of these factors on efficiency of PDX formation will allow for pervasive integration of these models in care of colorectal cancer patients. Mol Cancer Ther; 16(7); 1435-42. ©2017 AACR

<i>In-vitro</i> effects of O-ASC on the proliferation of multiple ovarian cancer cell lines.

<p>Luciferase expressing ovarian cancer cell lines were cultured alone or in a 1:1 ratio with unlabeled O-ASCs. Significant difference between controls (cancer cells cultured alone) and cancer cells co-cultured with O-ASCs are shown: *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 (n = 5). ANOVA with a Bonfferoni multiple comparisons test.</p

Chemoprotective and radioprotective effect of O-ASCs on ovarian cancer cell lines.

<p>Ovarian cancer cells were cultured with or without an equal number of O-ASC and treated with the doses of paclitaxel and carboplatin (n = 5) (A) or radiation (n = 4) 0-8 Gray (B) as shown. Significant differences are shown as follows: *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 for unpaired 2-tailed Student’s t-test.</p

Metabolic characterization of bone marrow-derived and adipose derived mesenchymal stem cells.

<p>Metabolic analysis was performed on BM-MSC, SC-ASC and O-ASC1 and 4, including glucose uptake (A), lactate secretion (B), pyruvate uptake (C), endogenous ATP production (D), ATP derived from glycolysis (E) and ATP derived from oxidative phosphorylation (OXPHOS)(F). Data are presented as mean ± S.E.M. *p<0.05, **p<0.01 and ***p< 0.001 for unpaired 2-tailed Student’s t-test (n = 8). </p

O-ASC increase the migration of ovarian cancer cells.

<p>Ovarian cancer cells migrated through a 8 μm pore in the presence of control of O-ASC conditioned media. The absorbance at 590 nm reflects the number of cells that passed through the transwell membrane. Significant differences are shown as follows: *, P < 0.05; **, P < 0.01; ***, P < 0.001 for unpaired 2-tailed Student’s t-test (n = 3).</p

Gene expression profiling of O-ASC as compared to BM-MSC and SC-ASC.

<p>Unsupervised clustering was performed to generate a dendrogram using center correlation and average linkage (A) (O-ASC1, O-ASC4, O-ASC5, BM-MSC: n = 2; SC-ASC: n = 4). IPA analysis revealed pathways with significantly different expression between O-ASC1 and O-ASC4 (B). Functions are listed from most significant (higher bars) to least significant (lower bars), and the perpendicular yellow line denotes the threshold for significance (P=0.05). </p