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Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
Published on: April 29, 2014
Kidney injury molecule-1 inhibits metastasis of renal cell carcinoma
Jasper C Lee1,2, Demitra M Yotis1, Ji Yun Lee1,2
1Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Abstract:
Metastasis is present in approximately 30% of patients diagnosed with renal cell carcinoma (RCC) and is associated with a 5-year survival rate of < 15%. Kidney injury molecule 1 (KIM-1), encoded by the HAVCR1 gene, is a proximal tubule cell-surface glycoprotein and a biomarker for early detection of RCC, but its pathophysiological significance in RCC remains unclear. We generated human and murine RCC cell lines either expressing or lacking KIM-1, respectively, and compared their growth and metastatic properties using validated methods. Surprisingly, KIM-1 expression had no effect on cell proliferation or subcutaneous tumour growth in immune deficient (Rag1-/-) Balb/c mice, but inhibited cell invasion and formation of lung metastasis in the same model. Further, we show that the inhibitory effect of KIM-1 on metastases was observed in both immune deficient and immune competent mice. Transcriptomic profiling identified the mRNA for the pro-metastatic GTPase, Rab27b, to be downregulated significantly in KIM-1 expressing human and murine RCC cells. Finally, analysis of The Cancer Genome Atlas (TCGA) data revealed that elevated HAVCR1 mRNA expression in the two most common types of RCC, clear cell and papillary RCC, tumours correlated with significantly improved overall patient survival. Our findings reveal a novel role for KIM-1 in inhibiting metastasis of RCC and suggests that tumour-associated KIM-1 expression may be a favourable prognostic factor.
Insights
Kidney injury molecule 1 (KIM-1) inhibits renal cell carcinoma (RCC) metastasis. Higher KIM-1 expression in RCC tumors correlates with better patient survival, suggesting it is a favorable prognostic factor.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Metastasis occurs in ~30% of renal cell carcinoma (RCC) patients, with a poor 5-year survival rate (<15%).
- Kidney injury molecule 1 (KIM-1), encoded by HAVCR1, is a biomarker for early RCC detection, but its role in RCC pathophysiology is unknown.
Purpose of the Study:
- To investigate the pathophysiological role of KIM-1 in renal cell carcinoma (RCC) metastasis.
- To determine if KIM-1 expression impacts RCC cell growth, invasion, and metastatic potential.
Main Methods:
- Generated human and murine RCC cell lines with and without KIM-1 expression.
- Assessed cell proliferation, subcutaneous tumor growth, and lung metastasis formation in immunocompromised mice.
- Performed transcriptomic profiling to identify molecular mechanisms.
- Analyzed The Cancer Genome Atlas (TCGA) data for correlation between HAVCR1 expression and patient survival.
Main Results:
- KIM-1 expression did not affect RCC cell proliferation or subcutaneous tumor growth.
- KIM-1 significantly inhibited RCC cell invasion and lung metastasis formation in both immunocompromised and immunocompetent mice.
- Transcriptomic analysis revealed downregulation of the pro-metastatic GTPase Rab27b mRNA in KIM-1 expressing RCC cells.
- Elevated HAVCR1 mRNA expression in clear cell and papillary RCC tumors correlated with improved overall patient survival.
Conclusions:
- Tumor-associated KIM-1 expression inhibits renal cell carcinoma (RCC) metastasis.
- KIM-1 acts as a novel inhibitory factor against RCC spread.
- Elevated KIM-1 levels in RCC tumors may indicate a favorable prognostic outcome for patients.
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