Abstract 2653: Cell proliferation and Cathepsin L expression are inversely correlated in bladder cancer progression and patient survival
Authors: Douglass Larry E. , Robillard Michelle C. , Stelzer Dan , Dooley Mariah , Deddens James A. , Carter Julia H. 
Published: August 2018

Abstract
In 2017 there will be an estimated 79,000 new cases of bladder cancer (UBC) resulting in 16,870 deaths. A better understanding of UBC progression and prognostic factors could improve patient management. UBC anatomic stage is determined by depth of invasion. Stage 0 is non-invasive, Stage 1 invades the sub-mucosa, Stage 2 invades the detrusor muscle, Stage 3 invades perivesical fat, and Stage 4 invades local or distant organs. 70-80% of UBCs are superficial, but can recur locally and be multifocal. Muscle invasive bladder cancers (MIBCs) can metastasize to pelvic lymph nodes or distant organs. To better understand the molecular mechanisms of UBC progression we measured cell proliferation utilizing the molecular marker of proliferating cells Ki 67 (Dako) and immunohistochemically detected expression of the lysosomal cysteine proteinase Cathepsin L (Abcam) in archived surgical specimens from 145 UBC patients. A board certified pathologist diagnosed and graded each histologic specimen and marked three areas for photography and image analysis. Clinical information and follow-up was obtained from existing medical records and the Kentucky Cancer Registry. IRB approval for the study was obtained from St. Elizabeth Healthcare who also donated the FFPE surgical specimens. We hypothesized that the % of proliferating tumor cells would increase with loss of cell differentiation and that Cathepsin L expression would increase with depth of tumor invasion into and beyond the detrusor muscle. Patients with high grade tumors (Grades 3 and 4) had a poor survival compared to patients with low grade tumors (p &lt; 0.0001) and patients with MIBC (Stages 2-4) had a poorer survival that patients with superficial tumors (Stages 0 - 1) (p &lt; 0.0001, HR = 18.63). Cell proliferation as determined by % of Ki 67 labeled nuclei was highly correlated with stage and grade (p &lt;0.0001). In contrast Cathepsin L expression measured either semi-quantitatively by histoscore (area X intensity of stain) or quantitatively by computer assisted image analysis was negatively correlated with stage, grade, and Ki 67 labeling (p &lt;0.0001). Recently multiple subtypes of MIBC have been identified, including basal tumors with squamous differentiation and luminal tumors. The highest rate of cell proliferation and the lowest expression of Cathepsin L in our data set were found in MIBC with squamous differentiation. Ki 67 labeling in UBC was highly prognostic of poor patient survival (p = 0.0003), whereas Cathepsin L expression as measured either by histoscore or image analysis was highly prognostic of good patient survival (p &lt; 0.0001). Since Cathepsin L is encoded by the CTSL gene located on chromosome 9, these data are consistent with published reports of frequent genetic loss and mutations of chromosome 9 in UBC. These data also strongly support the value of UBC cell proliferation as a prognostic marker for stratifying UBC patients.
Citation Format: Larry E. Douglass, Michelle C. Robillard, Dan Stelzer, Mariah Dooley, James A. Deddens, Julia H. Carter. Cell proliferation and Cathepsin L expression are inversely correlated in bladder cancer progression and patient survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2653.