Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Dec;26(12):R673-R688.
doi: 10.1530/ERC-19-0347.

Epigenetic Changes in Fibroblasts Drive Cancer Metabolism and Differentiation

Affiliations
Free PMC article
Review

Epigenetic Changes in Fibroblasts Drive Cancer Metabolism and Differentiation

Rajeev Mishra et al. Endocr Relat Cancer. .
Free PMC article

Abstract

Genomic changes that drive cancer initiation and progression contribute to the co-evolution of the adjacent stroma. The nature of the stromal reprogramming involves differential DNA methylation patterns and levels that change in response to the tumor and systemic therapeutic intervention. Epigenetic reprogramming in carcinoma-associated fibroblasts are robust biomarkers for cancer progression and have a transcriptional impact that support cancer epithelial progression in a paracrine manner. For prostate cancer, promoter hypermethylation and silencing of the RasGAP, RASAL3 that resulted in the activation of Ras signaling in carcinoma-associated fibroblasts. Stromal Ras activity initiated a process of macropinocytosis that provided prostate cancer epithelia with abundant glutamine for metabolic conversion to fuel its proliferation and a signal to transdifferentiate into a neuroendocrine phenotype. This epigenetic oncogenic metabolic/signaling axis seemed to be further potentiated by androgen receptor signaling antagonists and contributed to therapeutic resistance. Intervention of stromal signaling may complement conventional therapies targeting the cancer cell.

Keywords: endocrine therapy resistance; neuroendocrine tumors; prostate.

Figures

Figure 1
Figure 1
Heatmap summarizing DNA methylation levels of CpG repeats (blue color indicates hypomethylation and brown represents hypermethylation). (A) Hierarchical clustering and heatmap were generated for logarithmically transformed RRBS data and a columnwise normalization using MetaboAnalyst 3.0. (B) Tumor suppressor and (C) oncogenes identified from top 200 methylated genes differentially expressed between NAF and CAF are indicated. Each column represents a fibroblast sample, and each row represents the methylation level of indicated gene (n = 5).
Figure 2
Figure 2
A general scheme of epigenetic changes in fibroblasts include four basic mechanisms: (I) promoter DNA modifications, (II) histone modifications, (III) chromatin remodeling with polycomb proteins, and (IV) aberrant expression of miRNA. These well-known epigenetic modifications taking place in the tumor microenvironment can lead to transcriptomic changes, that in-turn can be suppressive of promoting of tumor expansion in a paracrine manner.
Figure 3
Figure 3
The expression levels of human RASAL1, RASAL2, RASAL3 and DAB2IP are profiled across multiple cancer types, compared to normal tissue by Oncomine. The gene expression level differences between cancer and normal tissue are illustrated. The number of datasets in which statistically significant mRNA overexpression or under-expression was observed is indicated in red or blue boxes, respectively. The color intensity corresponds to the gene rank and magnitude of expression differences with a statistically significant threshold.
Figure 4
Figure 4
Proposed model of stromal induced-neuroendocrine prostate cancer (NEPC). Carcinoma-associated fibroblasts (CAFs)-derived glutamine that can be taken-up by glutamine transporter, SLC1A5, and result in elevated mTOR signaling. Typical disease markers including chromogranin A (CHGA), FOXM1 and FOXA2 are shown upregulated after glutamine uptake in response to mTOR signaling. Inhibition of glutamine uptake by using SLC1A5 inhibitor, GPNA, limit the expression of NEPC markers. The studies suggest the importance of glutamine in NEPC transdifferentiation of prostate adenocarcinoma (Mishra et al. 2018).

Similar articles

See all similar articles

References

    1. Adjei AA. 2001. Blocking oncogenic Ras signaling for cancer therapy. Journal of the National Cancer Institute 1062–1074. (10.1093/jnci/93.14.1062) - DOI - PubMed
    1. Albrengues J, Bertero T, Grasset E, Bonan S, Maiel M, Bourget I, Philippe C, Herraiz Serrano C, Benamar S, Croce O, et al. 2015. Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nature Communications 10204 (10.1038/ncomms10204) - DOI - PMC - PubMed
    1. Allocati N, Masulli M, Di Ilio C, Federici L. 2018. Glutathione transferases: substrates, inhibitors and pro-drugs in cancer and neurodegenerative diseases. Oncogenesis 8 (10.1038/s41389-017-0025-3) - DOI - PMC - PubMed
    1. Altman BJ, Stine ZE, Dang CV. 2016. From Krebs to clinic: glutamine metabolism to cancer therapy. Nature Reviews: Cancer 749 (10.1038/nrc.2016.114) - DOI - PubMed
    1. Banerjee J, Mishra R, Li X, Jackson RS, 2nd, Sharma A, Bhowmick NA. 2014. A reciprocal role of prostate cancer on stromal DNA damage. Oncogene 4924–4931. (10.1038/onc.2013.431) - DOI - PMC - PubMed

LinkOut - more resources

Feedback