Abstract 192: Role of adipose tissue in bladder cancer progression

Abstract

Abstract Introduction: Obesity has been found to be associated with increased risk of bladder cancer, worse-cancer-specific outcomes and increased risk of recurrence. Moreover, bladder cancers that involve macroscopic extravesical invasion of the perivesical fat are highly predisposed to lymph node metastases and local recurrence. The objective of our study is to elucidate the mechanism by which adipose tissue contributes to bladder cancer progression. We hypothesize that adipose tissue in bladder cancer patients has the potential to modulate the tumor microenvironment by inducing pro-tumorigenic pathways in bladder cancer progression. Methods: Human adipose tissue fragments (bladder, urachal, subcutaneous and prostate when applicable) were collected from muscle-invasive bladder cancer (MIBC) patients undergoing cystectomy. Information on patient Body Mass Index (BMI), diabetes diagnosis, medications and gender were used in analysis. BMI status was classified into normal (under 25 kg/m2), overweight (25-29.9 kg/m2) and obese (≥30 kg/m2). Gene expression was profiled from total RNA isolated from 100mg of fat using the Illumina Human HT12 whole genome expression BeadChips. Fat conditioned media (CM) was prepared from 500 mg of the patient fat processed as primary adipose tissue explant cultures for 16 hours. Secreted factors from CM were measured using MILLIPLEX MAP 41-plex Human Cytokine/Chemokine Panel. Migratory potential was assayed by Transwell (BD falcon) migration. T24 human bladder cancer cells were placed in the upper chamber with patient fat CM or control serum free media in the lower chamber. Cells were allowed to transmigrate across the porous membrane for 18 hours. Results: At the genomic level in fat specimens from twelve cancer patients with different BMI status indicated a number of differentially expressed genes previously implicated in cancer progression. The expression of CCL3/macrophage inflammatory protein-1α (a secreted protein) and matrix metalloproteinase-9 are significantly upregulated in fat samples from obese and overweight patients relative to normal. At the protein level in CM, three factors: interleukin-8, growth regulated oncogene-alpha and monocyte chemotactic protein-1, are found in high levels across all patient tissue depots. Surprisingly, exposing T24 cells to CM from bladder fat depots increased their migratory potential. Ongoing studies are evaluating the specific factors involved in this difference. Conclusions: The identified differentially expressed genes and secreted factors provide a possible mechanism to explain the effects of obesity on tumor progression in bladder cancer. In addition to BMI, the migratory potential of T24 cells was also differentially modulated by the different fat deposit types. Ongoing studies are investigating the effect of adipose tissue-derived factors on bladder cancer to help improve outcome in advance bladder cancer patients with added complexities of obesity. Citation Format: Nisha Hariharan, Robert S. Svatek, Carolina B. Livi, Jonathan A.L. Gelfond, Teresa L. Johnson-Pais, Robin J. Leach. Role of adipose tissue in bladder cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 192. doi:10.1158/1538-7445.AM2014-192