DNA Damage Induces a Secretory Program in the Quiescent TME that Fosters Adverse Cancer Phenotypes

Abstract

Carcinomas develop in complex environments that include a diverse spectrum of cell types that influence tumor cell behavior. These microenvironments represent dynamic systems that contribute to pathological processes. Damage to DNA is a notable inducer of both transient and permanent alterations in cellular phenotypes. Induction of a DNA-damage secretory program is known to promote adverse tumor cell behaviors such as proliferation, invasion, metastasis, and treatment resistance. However, prior studies designed to identify genotoxic stress-induced factors evaluated actively proliferating in vitro cultures of cells such as fibroblasts as experimental models. Conversely, the vast majority of benign cells in a typical tumor microenvironment (TME) are not proliferating, but rather exist in quiescent (i.e., G0) or in terminally-differentiated states. In this study, the diversity and magnitude of transcriptional responses to genotoxic damage in quiescent prostate fibroblasts were assessed using gene expression profiling. The secretory damage response in quiescent cells was highly concordant with that of actively dividing cells. Quiescent human prostate stroma exposed to genotoxic agents (e.g., mitoxantrone) in vivo resulted in significant upregulation (2.7-5.7 fold; (p≤0.01) of growth factors and cytokines including: IL-1β, MMP3, IL-6, and IL-8. The paracrine effects of damaged quiescent cells consistently increased the proliferation and invasion of prostate cancer cells and promoted cell survival and resistance to apoptosis following exposure to chemotherapy. Implications Benign quiescent cells in the TME respond to genotoxic stress by inducing a secretory program capable of promoting therapy resistance. Developing approaches to suppress the secretory program may improve treatment responses.

EB virus-induced ATR activation accelerates nasopharyngeal carcinoma growth via M2-type macrophages polarization

“…), and promote the transformation of macrophages to M2, hinting that viral infection might play an important role in the macrophage M2-type polarization. Meanwhile, viral infection could also regulate the polarization of TAMs via inducing DDR [15][16][17] . For example, ATR mutations lead to the decreased T cell recruitment, stimulate the increase in the number of M2 macrophages associated with tumor invasion and promote melanoma growth 18 , indicating that endogenous ATR mutations results in M2 TAMs accumulation.…”

Predictive value of epithelial‐mesenchymal‐transition (EMT) signature and PARP‐1 in prostate cancer radioresistance

“…Radiation treatment has been shown to program changes in the tumor microenvironment facilitating prostate cancer progression and disease recurrence . Survival of tumor cells after exposure to radiation is dependent on the integration of innate damage response capabilities and the tumor microenvironment .…”

“…22,23 Radiation treatment has been shown to program changes in the tumor microenvironment facilitating prostate cancer progression and disease recurrence. 24,25 Survival of tumor cells after exposure to radiation is dependent on the integration of innate damage response capabilities and the tumor microenvironment. 9,25 Poly (ADP-ribose)-ylation polymerase-1, PARP-1, is an abundant and ubiquitous enzyme found predominantly in the nucleus, functionally involved in DNA damage repair and transcription factor regulation, 26 via activating its recruitment (PARP-1) of DNA repair proteins to sites of nuclear damage.…”

“…24,25 Survival of tumor cells after exposure to radiation is dependent on the integration of innate damage response capabilities and the tumor microenvironment. 9,25 Poly (ADP-ribose)-ylation polymerase-1, PARP-1, is an abundant and ubiquitous enzyme found predominantly in the nucleus, functionally involved in DNA damage repair and transcription factor regulation, 26 via activating its recruitment (PARP-1) of DNA repair proteins to sites of nuclear damage. 27 Diverse lines of mechanistic evidence suggest a critical role for PARP-1 in prostate cancer via its ability to transcriptionally regulate functionally critical genes contributing to tumor growth, progression to CRPC and metastasis and radioresistance.…”

Transcriptome analysis of differentially expressed genes and pathways associated with mitoxantrone treatment prostate cancer

“…The accumulation of DNA lesions leads to genomic instability through chromosomes breaks, amplification of oncogenes and inactivation of tumour suppression genes, driving to the acquisition of a malignant cancer phenotype. 6 However, cancer cells can overcome DNA damage by induction of a DNA damage secretory program such as proliferation, invasion, metastasis, especially treatment resistance can develop through a variety of signal pathways, including base excision repair, nucleotide excision repair, mismatch repair, direct repair and recombinational repair. 7,8 Comparative genomic hybridization can help to identify relevant genes involved in tumour chemotherapy-resistance and to predict response and cancer prognosis.…”