From stress to cancer: beware of "dormant" cells awakening

Abstract: what does science say?

Recent research suggests that neuroendocrine signals related to stress (catecholamines and glucocorticoids) can modify neutrophil function and the tissue environment, promoting the release of inflammatory molecules such as S100A8/A9 proteins and the formation of neutrophil extracellular traps (NETs). In animal models, these processes have been linked to the reactivation of "dormant" tumor cells and metastasis formation. Observational studies in human samples show associations between inflammatory markers and recurrence, while meta-analyses on adrenergic drugs (beta-blockers) provide heterogeneous results. Biological evidence is solid at the experimental level, but clinical translation requires confirmation with prospective studies and controlled trials.

Definition and scope of the problem

Dormant tumor cells are disseminated cells that, after detaching from the primary tumor, can remain in a quiescent state for months or years. If reactivated, they can lead to recurrence or metastasis. Scientific interest is growing because understanding the signals that cause reactivation offers possibilities for long-term recurrence prevention and new therapeutic targets.

What experimental evidence shows

Murine models and cell cultures have shown that exposure to stress hormones (e.g., norepinephrine) can stimulate neutrophils to release S100A8/A9 and generate modified lipids that promote the proliferation of dormant cells. In these models, inhibition of the adrenergic pathway or removal of neutrophils reduces the "awakening" effect observed [1]. In parallel, research on pulmonary inflammation indicates that NETs, through extracellular matrix degradation, can expose epitopes that activate integrins and pro-proliferative pathways, leading to the reactivation of dormant cells [2].

Epidemiological and clinical context

Analyses in small groups of lung cancer patients have shown that higher blood levels of S100A8/A9 after surgery are associated with a higher probability of medium-term recurrence, but these are observations on limited samples and with possible confounding factors [1]. Observational studies on chronic use of beta-blockers report conflicting results: some meta-analyses indicate reductions in recurrence in particular contexts (for example, in some subtypes of breast cancer), while others find no overall benefit or show heterogeneity between tumors and types of beta-blockers [5].

Biological implications: connection with stress and oxidative stress

The plausible link between stress and tumor progression is supported by preclinical work showing how adrenergic activation increases angiogenesis and tumor invasiveness via cAMP/PKA and the production of factors like VEGF [3]. In parallel, oxidative stress (ROS) is implicated in both DNA damage and the modulation of immune responses: its action can be protective or promotional depending on the context and intensity, making the interpretation of its effects in carcinogenesis and progression complex [7][8].

Limitations and levels of evidence

Experimental evidence (animal models, cells) is robust for outlining possible mechanisms; however, correlations in human studies remain largely observational, with a risk of confounding, limited sample sizes, and variable exposure measures. For clinical practice, prospective studies, biomarker validation in independent cohorts, and randomized trials are necessary when possible.