Abstract 5195: Kidney injury molecule-1: a novel therapeutic target in renal cell carcinoma.
Authors: Venkata Sabbisetti, Rupal Bhatt, Swetha Ramadesikan, Joseph Bonventre
Journal: Cancer Research (2013)

Abstract Background. Renal cell carcinoma (RCC) is characterized by lack of early warning signs, diverse clinical manifestations, absence of a reliable diagnostic and predictive biomarker, and resistance to targeted therapy. Thus, novel approaches for diagnosis, management and treatment of RCC are urgently needed. Kidney Injury Molecule-1 (KIM-1) is not expressed in normal kidney tissues but markedly up-regulated in dedifferentiated proximal tubular epithelial cells following renal injury. We demonstrated that KIM-1 is expressed ubiquitoulsy by both primary and metastatic lesions of clear cell and papillary renal cell carcinoma, while barely detectable in other subtypes of RCC. Additionally, the ectodomain of KIM-1 is cleaved by matrix metalloproteinases and sheds into the surrounding milieu. Methods. KIM-1 was stably transfected in immortalized renal tubular epithelial cells (LLC-PK1, gain-of-function) and KIM-1 was downmodulated in RCC cell lines (loss-of-function) using a siRNA lentiviral approach. KIM-1 function was assessed using these two systems. Results. Stable expression of KIM-1 in non-malignant renal epithelial cells increased cell proliferation, migration and invasion potential, induced anchorage independent growth, and increased the secretion of tumor promoting and angiogenic factors including VEGF, Ang2, TGF beta and IL-6 (PK1-KIM-1); while depletion of KIM-1 in RCC cells led to G1 cell cycle arrest phase and senescence. Recently, we and others have demonstrated that KIM-1 is a phosphatildyl serine receptor and the expression of KIM-1 converts a normal epithelial cell into a “semi professional phagocyte” and facilitates the removal of apoptotic and necrotic cells by recognizing phosphotidyl serine (PS) on their cell surface. Our data suggests that during this process, tumor epithelial cells undergo reprogramming and secrete and activate cytokines involved in cell survival and angiogenesis programs. Conclusions. The present study shows that KIM-1-expression promotes tumorigenesis primarily by two distinct mechanisms: i) by directly conferring oncogenic properties to renal epithelial cells; ii) by resulting in production of a variety of chemokines and cytokines that support tumor progression and angiogenesis. We believe that our findings can significantly contribute to the development of novel therapeutic apporaches and in the advancement of management strategies in RCC and help reduce associated mortality and morbidity. Citation Format: Venkata Sabbisetti, Rupal Bhatt, Swetha Ramadesikan, Joseph Bonventre. Kidney injury molecule-1: a novel therapeutic target in renal cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5195. doi:10.1158/1538-7445.AM2013-5195 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.