Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, ...and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454‐489.
Prostate cancer is a leading cause of cancer and cancer-related mortality in males in the United States. Acid ceramidase is frequently overexpressed in prostate cancer and catalyzes the deacylation ...of proapoptotic ceramide into sphingosine. Sphingosine is converted by sphingosine kinases into sphingosine 1-phosphate, which promotes numerous pro-cancer phenotypes. Due to the frequent overexpression of acid ceramidase in prostate cancer and its net cancer promoting signaling effects achieved by reducing ceramide and generating sphingosine 1-phosphate, the impact of acid ceramidase, and the lipid profiles it alters, on prostate cancer cell signaling were studied. Here we report the activation of the oncogenic P131(/Akt signaling pathway when acid ceramidase is overexpressed both in human prostate tissue and in prostate cancer cell lines. This effect was found to depend on sphingosine kinase I; potentially reflecting increased accessibility of sphingosine kinase 1 to lysosome-derived sphingosine. Surprisingly, we found that SIP receptor 2 mediates acid ceramidase-induced Akt activation, which challenges the prevailing view in the literature that suggests predominantly tumor suppressive functions for SIP receptor 2. Functionally, acid ceramidase overexpressing cells were found to be resistant to cytotoxic chemotherapies, but profoundly sensitive to inhibition of PI3K or Akt in proliferation assays and soft agar colony formation, suggesting acid ceramidase overexpressing cells become dependent on Akt signaling for their oncogenic phenotypes. The tumor suppressor PTEN classically antagonizes P13K-mediated activation of Akt, however emerging evidence suggests that nuclear PTEN is also critically important in suppressing cancer. Thus, mechanisms mediating nucleocytoplasmic shuttling of PTEN are of great interest. Following observations that acid ceramidase promoted net redistribution of PTEN from the nucleus into the cytoplasm, we found that the AC-induced Akt activation pathway described above also promoted nuclear egress of PTEN. Furthermore, we found that acid ceramidase and sphingosine 1-phosphate promote formation of a complex between Crm1 and PTEN, confirming that acid ceramidase promotes Crml-mediated active export of PTEN. After investigating several potential mechanism including PTEN C-terminus phosphorylation and direct export through an in silico predicted PTEN nuclear export sequence, we found that acid ceramidase promotes PTEN nuclear export dependent upon Akt-mediated activation of S6K. Functionally, we found that acid ceramidase was able to promote resistance to Docetaxel chemotherapy, cell proliferation, and tumor formation in cells expressing wild type PTEN, but not in cells expressing nuclear localized PTEN, suggesting that acid ceramidase promotes prostate cancer in part through Akt-mediated nuclear export of PTEN.
