Lineage relationship of prostate cancer cell types based on gene expression

Abstract

Background: Prostate tumor heterogeneity is a major factor in disease management. Heterogeneity could be due to multiple cancer cell types with distinct gene expression. Of clinical importance is the so-called cancer stem cell type. Cell type-specific transcriptomes are used to examine lineage relationship among cancer cell types and their expression similarity to normal cell types including stem/progenitor cells.

Methods: Transcriptomes were determined by Affymetrix DNA array analysis for the following cell types. Putative prostate progenitor cell populations were characterized and isolated by expression of the membrane transporter ABCG2. Stem cells were represented by embryonic stem and embryonal carcinoma cells. The cancer cell types were Gleason pattern 3 (glandular histomorphology) and pattern 4 (aglandular) sorted from primary tumors, cultured prostate cancer cell lines originally established from metastatic lesions, xenografts LuCaP 35 (adenocarcinoma phenotype) and LuCaP 49 (neuroendocrine/small cell carcinoma) grown in mice. No detectable gene expression differences were detected among serial passages of the LuCaP xenografts.

Results: Based on transcriptomes, the different cancer cell types could be clustered into a luminal-like grouping and a non-luminal-like (also not basal-like) grouping. The non-luminal-like types showed expression more similar to that of stem/progenitor cells than the luminal-like types. However, none showed expression of stem cell genes known to maintain stemness.

Conclusions: Non-luminal-like types are all representatives of aggressive disease, and this could be attributed to the similarity in overall gene expression to stem and progenitor cell types.

Figure 1

Principal components analysis of prostate ABCG2⁺ cells. A: This human prostate PCA space is keyed on the transcriptomes of B, L, S, and E cells. Stem cell transcriptome is represented by that of NCCIT. Putative progenitor cells sorted from the prostate by antibody to ABGC2 (clone 5D3) or in SP are shown. Many 5D3 sorts (red cubes) are found to cluster near E except for that derived from specimen 04-126. This and two SPs are positioned nearer the NCCIT. B: The expression levels of CD133 and CD31 in 04-126, other 5D3 sorts (labeled as "5D3"), endothelial sorts (labeled as CD31+) and SP are indicated by array signal values on a gray scale in the data query display. The histograms below show the same query output. Note the different expression magnitude scales on the y-axis for the two genes.

Figure 2

Gene expression comparison of ABCG2⁺ cells and stem cells. A: Differential expression of selected genes between 5D3 (04-126), SP and ES (H1) and EC (NCCIT) cells as obtained from dataset query is shown. B: PCA plot of H1 and NCCIT shows the close relatedness between these two cell types.

Figure 3

LuCaP xenograft gene expression. Displayed are the expression patterns of selected genes (listed in the first column) in the two LuCaP xenografts with individual datasets identified by their passage numbers p.

Figure 4

PCA of prostate cancer cell types. A: Transcriptomes of prostate primary cancer G3, G4, cell lines LNCaP, C4-2, CL1, DU145, PC3, xenografts LuCaP 35, LuCaP 49 are projected into the space defined by B-L-S-E. The CL1 data point also contains transcriptomes from CL1 subclones. B: Panel A shows grouping of the so-called luminal-like cancer cell types, while panel B shows grouping of the non-luminal-like cancer cell types in a different viewing aspect.

Figure 5

Differential gene expression among cancer cell types. A: Shown is the dataset query display of selected genes among the cell types listed. B: Shown is the query display for seven selected genes among the non-luminal-like cancer cell types.

Figure 6

Prostate tumor CD44 and CD133 expression. Dataset identities in the histograms are indicated on the x-axis. Red is that of 05-179 CD26⁺ G3 cancer cells, which shows absent CD44 and CD133 expression.