Abstract
BackgroundLoss of prostate cancer differentiation or de-differentiation leads to an untreatable disease. Patient survival would benefit if this can be prevented or reversed. Cancer de-differentiation transforms luminal-like (differentiated) adenocarcinoma into less luminal-like and more stem-like (undifferentiated) small cell carcinoma through a sequential activation of stem cell transcription factors (scTF) POU5F1, LIN28A, SOX2 and NANOG. Like stem cells, prostate small cell carcinoma express this quartet of scTF as well as a 10-fold lower level of β2-microglobulin (B2M) than that of differentiated cell types. In organ development, prostate stromal mesenchyme cells mediate epithelial differentiation in part by secreted factors.MethodsThe identified prostate stromal-specific factor proenkephalin (PENK) was cloned, and transfected into scTF+B2Mlo stem-like small cell carcinoma LuCaP 145.1, reprogrammed luminal-like scTF−B2Mhi LNCaP, and luminal-like scTF−B2Mhi adenocarcinoma LuCaP 70CR. The expression of scTF, B2M and anterior gradient 2 (AGR2) was analyzed in the transfected cells.ResultsPENK caused down-regulation of scTF and up-regulation of B2M to indicate differentiation. When transfected into reprogrammed LNCaP, PENK reversed the reprogramming by down-regulation of scTF with attendant changes in cell appearance and colony morphology. When transfected into LuCaP 70CR, PENK up-regulated the expression of adenocarcinoma antigen AGR2, a marker associated with cancer cell differentiation.ConclusionsProstate cancer cells appear to retain their responsiveness to stromal PENK signaling. PENK can induce differentiation to counter de-differentiation caused by scTF activation. The many mutations and aneuploidy characteristic of cancer cells appear not to hinder these two processes. Loss of prostate cancer differentiation is like reprogramming from luminal-like to stem-like.
Highlights
Loss of prostate cancer differentiation or de-differentiation leads to an untreatable disease
Shown are d0 when Patient-derived xenograft lines (LuCaP) 145.1 cells were obtained after processing, and d2 when the cells were harvested by trypsin treatment for DNA transfection
LuCaP 145.1 cells banded at the [strom] density in Percoll, no outgrowth of mouse fibroblasts that might be present in the tumor specimen was seen
Summary
Loss of prostate cancer differentiation or de-differentiation leads to an untreatable disease. Prostate stromal proenkephalin (PENK) was identified by a comparative transcriptome analysis between sorted CD49a+ prostate stromal cells and CD13+ bladder stromal cells of the lamina propria [2], the rationale being that genes encoding these molecules are likely organ specific (i.e., either prostate or bladder). Immunostaining with a PENK polyclonal antibody raised against the peptide sequence T163-E179 detected strong reactivity in the stroma of benign prostate tissue and no reactivity in the bladder lamina propria [2]. This result validated the RNA expression analysis. Prostate stromal cells are not known as a source of these opioids
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