Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments

Abstract

Hypoxia is a poor-prognosis microenvironmental hallmark of solid tumours, but it is unclear how it influences the fate of disseminated tumour cells (DTCs) in target organs. Here we report that hypoxic HNSCC and breast primary tumour microenvironments displayed upregulation of key dormancy (NR2F1, DEC2, p27) and hypoxia (GLUT1, HIF1α) genes. Analysis of solitary DTCs in PDX and transgenic mice revealed that post-hypoxic DTCs were frequently NR2F1hi/DEC2hi/p27hi/TGFβ2hi and dormant. NR2F1 and HIF1α were required for p27 induction in post-hypoxic dormant DTCs, but these DTCs did not display GLUT1hi expression. Post-hypoxic DTCs evaded chemotherapy and, unlike ER− breast cancer cells, post-hypoxic ER+ breast cancer cells were more prone to enter NR2F1-dependent dormancy. We propose that primary tumour hypoxic microenvironments give rise to a subpopulation of dormant DTCs that evade therapy. These post-hypoxic dormant DTCs may be the source of disease relapse and poor prognosis associated with hypoxia.

STAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cells

“…Similar results were obtained when NOD-SCID mice were injected s.c. with 1 × 10 4 A375 melanoma TRCs and treated with or without IFN-β (75 ng per d) in the presence or absence of anti-IFN-β antibody (Supplemental Figure 1, E and F). In addition, we immunostained the above tissue with the dormant markers (NR2F1/Ki67 or DEC2/Ki67) as reported (28,29) and found that IFN-β treatment remarkably increased the percentage of NR2F1 Figure 1G), further confirming that IFN-β-treated melanoma cells are in a dormant state. Together, these data suggest that IFN-β treatment is capable of inducing stem-like melanoma cells into dormancy in vivo.…”

The Different Routes to Metastasis via Hypoxia-Regulated Programs

“…Sustained hypoxia in a growing tumor was described as being associated with a clinically aggressive phenotype, increased invasive capacity, perifocal tumor cell spreading, regional and distant dissemination, and resistance to different therapies [4,5]. However, hypoxia can also induce growth arrest, cause cell death, decrease motility speed while increasing invasiveness and directionality [6], and induce a dormancy-like program [7]. …”

“…Intriguingly, the UPR was found in dormant cancer cells in experimental models [111] and transcripts for speci c UPR genes were also found to be upregulated in dormant DTCs isolated from BM of prostate cancer patients [112]. These genes could also be turned on in DTCs in the target organ by the fact that they carry a signature epigenetically imprinted in the primary tumors (i.e., the DTCs carry a remodeled chromatin in response to hypoxia in the primary site) [7,113]. Accordingly, hypoxic micro-environments in primary lesions contain a fraction of cells that concomitantly turn on hypoxia (GLUT1 and HIF1a) and long-term dormancy genes such as NR2F1, DEC2, and p27.…”

“…Interestingly, this histone H3 repressive mark is found in dormant cells [114], suggesting that it could be a regulator of a persistent dormancy program retained in DTCs originating from hypoxic primary tumor niches. Importantly, hypoxia-induced dormant-like DTCs survive chemotherapy [7]. These findings lead to the notion that these once hypoxic and now dormant DTCs may be the source of disease relapse and poor prognosis associated with hypoxia.…”

Hypoxia-induced autophagy in hepatocellular carcinoma and anticancer therapy

“…Authors speculated that these DTCs may be the source of disease relapse and poor prognosis associated with hypoxia. [41] National Journal of Physiology, Pharmacy and Pharmacology 774 2017 | Vol 7 | Issue 8…”