Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination

Abstract

Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes.

COX2/mPGES1/PGE 2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

“…Recently published studies suggest that COX2/PGE 2 signaling is also important for the proliferation and renewal of bladder stem cancer cells (28). Macrophage-derived PGE 2 also promotes tumor cell dissemination, that is, spreading of metastatic malignant cell from parental tumor (29). Therefore, harnessing PGE 2 metabolism in the tumor-infiltrating myeloid cells, including tumor-associated macrophages and their predecessors MDSCs, could potentially exert the multipronged cancer therapeutic effects by (i) stimulating anti-tumor response through PD-L1 down-regulation and preserving function of immune T cells, (ii) attenuating renewal of cancer stem cells, and (iii) inhibiting metastatic cancer cell spreading.…”

Quantitative measurement of lymphatic function in mice by noninvasive near-infrared imaging of a peripheral vein

“…volumes (<30 μl) of blood could be repeatedly sampled from either the tail vein or saphenous vein in restrained unanesthetized mice (14); however, it is stressful for the animal and this may affect lymph flow (33,34). Short-term inhalation anesthesia could be used to limit this effect; however, at least in mice, the dynamics of lymph transport are relatively quick, which would require multiple anesthesia applications and blood samplings within a short period of time.…”

Cancer cells become less deformable and more invasive with activation of β-adrenergic signaling

“…Activation of β-adrenergic signaling is an emerging factor that promotes metastasis and accelerates cancer progression Sloan et al, 2010;Thaker et al, 2006). Cancer cells express β-adrenoceptors, whose activation results in increased invasion and metastasis in vivo (Creed et al, 2015;Le et al, 2016); this suggests that targeting the β-adrenergic signaling pathway might be a promising strategy to slow disease progression, especially for diseases such as triple-negative breast cancer and pancreatic cancer, which are often aggressive and have few treatment options once chemoresistance develops. Inhibition of β-adrenergic signaling is an especially promising therapeutic strategy: an effective antagonist for β-adrenergic receptors (βARs) are β-blocker drugs, which are already widely used to treat cardiac disease and hypertension (Barrese and Taglialatela, 2013;Wiysonge et al, 1996).…”

“…Inhibition of β-adrenergic signaling is an especially promising therapeutic strategy: an effective antagonist for β-adrenergic receptors (βARs) are β-blocker drugs, which are already widely used to treat cardiac disease and hypertension (Barrese and Taglialatela, 2013;Wiysonge et al, 1996). β-blockers inhibit metastasis in vivo (Campbell et al, 2012;Creed et al, 2015;Le et al, 2016;Sloan et al, 2010;Sood et al, 2006) and analyses of cancer patient cohort data has revealed that coincidental use of β-blockers is linked to reduced metastasis and improved survival (Barron et al, 2011;Le et al, 2016;Melhem-Bertrandt et al, 2011;Powe et al, 2010). Recent mechanistic studies show that β-adrenergic signaling modulates metastasis by driving changes in the tumor microenvironment including vascular remodeling and immune cell recruitment Thaker et al, 2006).…”