Proliferation and tissue remodeling in cancer: the hallmarks revisited

Abstract

Although cancers are highly heterogeneous at the genomic level, they can manifest common patterns of gene expression. Here, we use gene expression signatures to interrogate two major processes in cancer, proliferation and tissue remodeling. We demonstrate that proliferation and remodeling signatures are partially independent and result in four distinctive cancer subtypes. Cancers with the proliferation signature are characterized by signatures of p53 and PTEN inactivation and concomitant Myc activation. In contrast, remodeling correlates with RAS, HIF-1α and NFκB activation. From the metabolic point of view, proliferation is associated with upregulation of glycolysis and serine/glycine metabolism, whereas remodeling is characterized by a downregulation of oxidative phosphorylation. Notably, the proliferation signature correlates with poor outcome in lung, prostate, breast and brain cancer, whereas remodeling increases mortality rates in colorectal and ovarian cancer.

Figure 1

Proliferation and remodeling sub-signatures in controlled experiments. Heatmaps showing the proliferation and remodeling signatures in control experiments. The red indicates a significant upregulation, black no association, and blue a significant downregulation of the signature indicated on the right. (a) Induction of cell proliferation with IGF-I in MCF7 breast cancer cells, based on data from Creighton et al. (b) Induction of the EMT with TGF-β in A549 human lung adenocarcinoma cells, based on data from Sartor et al.

Figure 2

Gene expression signatures by P/R subtype. (a) Gene signatures expression in tumor samples from different cancer types. (b) Overall gene signature enrichment across cancer data sets by P/R subtype. In this heat map, a column represents the subset of tumors in the data set indicated in the bottom that were classified as the P/R subtype indicated in the top bar. A red color indicates that the signatures listed on the right is significantly enriched among the samples of that particular data set and subtype, the brighter the red the more significant, while the blue indicates the absence of a significant enrichment

Figure 3

Proliferation-remodeling impact on survival. Kaplan–Meier survival plots stratified by the P/R subtypes in different cancers. The panels (a-h) represent different cancer types as indicated on the top of each panel.