Abstract
I was recently surprised to hear a medical doctor on a TV show refute the role of stress in cancer, assuming that “the whole population would have cancer if this was the case.” This statement illustrates a long and winding road since Hippocrates suggested the potential relationship between cancer and psychologic disturbances. The 20th and 21st centuries have finally witnessed the evidence of how physical or psychosocial stress situations contribute to the development and progression of cancer, and it is now assumed that psychologic stress does affect multiple aspects of cancer such as angiogenesis, immunologic escape, invasion, and metastasis. The 2010 publication by Sloan and colleagues in Cancer Research achieved a mechanistic step toward the understanding of how physical distress enhances metastasis through perturbation of the tumor immune system and paves the way for future cancer research in psychoneuroimmunology. This Landmark commentary places this publication in the historical context of science, discusses major advances in the field, and asks questions to be answered while drawing perspectives on the key role of the peripheral and central nervous systems in cancer.
See related article by Sloan and colleagues, Cancer Res 2010;70:7042–52
In 2011, Mina Bissel inquired, “Why don't we get more cancer?” Her insights emphasized the cross-talk between the microenvironment and the heterogeneous genomic instability of cancer cells (1). She showed that signaling pathways that operate in a healthy given organ can be hijacked by precancerous cells to become cancerous and initiate a tumor. In accordance, the role of psychologic stress in cancer has been regularly discussed by scientists, partly based on clinical observations like how patients with cancer perceive the effect of stress on their body and whether stress can cause or modify their disease. In the 5th century BC, Hippocrates had already suggested that patients with psychologic disturbances such as depression (called melancholia at this time) would be more inclined to develop cancer and proposed the idea that tumors could be “melancholia-dependent.” Yet, the road toward the implementation of this topic in basic and preclinical science has taken several centuries. In 1975, a study by Vernon Riley published in Science showed that chronic environmental stressors on mice tend to increase breast tumor incidence and shorten the delay in tumor development initially observed when mice are preserved from any stressors. This study put forward that glucocorticoid release from activation of the hypothalamo–pituitary–adrenal (HPA) axis might impair antitumor immunity (2). However, the time had not yet come to consider the role of stress in cancer. It took decades for cancer scientists to identify stress-mediated signaling pathways involved in the development and progression of tumors. In 2006, Thaker and colleagues found, using preclinical cancer models, that stress-mediated activation of the sympathetic nervous system, which controls the release of catecholamines into the bloodstream by the adrenal medulla (called the sympathoadrenal system, SAS), promotes ovarian primary tumor growth (3). Mechanistically, they identified that, under chronic restraint stress, β-adrenergic signaling mediates the proliferation of Adrβ2-expressing cancer cells, leading to the growth of primary tumors, with a concomitant increase in tumor angiogenesis accompanied by an elevation of angiogenic molecules in tumor tissues. The concept of “pathway hijacking” featured by Mina Bissel was well illustrated in this case where autonomic and neuroendocrine pathways originating in the brain to preserve whole-body homeostasis in response to stressors are rerouted to help tumor development.
In this context, we find the landmark 2010 study by the group of Steven W. Cole at the University of California Los Angeles published in Cancer Research (4). Erika K. Sloan and coworkers showed, herein, in preclinical mouse cancer models, that chronic restraint stress does not affect primary tumor growth, but instead, promotes cancer metastasis through a systemic release of catecholamines that causes a significant increase in the number and size of metastases. Using a pharmacologic approach, the authors showed that the enhancement of metastasis depends on the activation of β-adrenergic signaling under stress and identified a possible path through changes in the tumor immune landscape. In addition, in the context of chronic stress, and using nonselective Adrβ agonist or antagonist, they showed that β-adrenergic signaling potentiates tumor immunity by a significant and selective recruitment of Adrβ2−expressing macrophages within primary tumor tissues, without any effect on other myeloid cells or alteration of T cells. Further analyses identified this population of macrophages as having a prometastatic and proinflammatory gene signature, similar to the phenotype of M2 macrophages, associated with the capability of promoting the development of blood vessels in primary tumors. In turn, nonselective pharmacologic inhibition of macrophages decreases stress-induced metastasis and angiogenesis in primary tumors. Yet, what is still unclear at this stage is why primary tumor growth seems unaffected by β-adrenergic signaling and the infiltration of Adrβ2-expressing macrophages within primary tumor masses while a direct effect of β-adrenergic pathway on the development of primary tumors had been reported earlier (2, 3). Nevertheless, this study identified an interesting relationship between psychologic stress, β-adrenergic signaling and the immune system in cancer, and established the rationale for further in-depth studies, especially now in the context of cancer immunotherapy, to elucidate mechanisms of resistance to immune checkpoint inhibitors.
The noxious role of stress hormone pathways in cancer is now well established and was complemented with the recent study published in 2019 by Obradovic and colleagues who identified the mechanism on how the HPA axis and glucocorticoid release may affect metastasis, and finally answered the question left open by Vernon Riley 44 years ago (5). However, at this stage, burning questions remain like which life situations, lifestyles, or stressors can increase cancer risk and lead to the development of a malignant tumor. Thus, besides the tumor microenvironment, physical and social environments, known to influence the well-being or physical and mental health of an individual, may affect cancer behavior. Psychosocial stressors induced by isolation of rats bearing breast cancer advance tumor growth and progression (6). Conversely, enriched living environments delay tumor growth and increase survival, suggesting that enriched environment conditions, such as social support and mental well-being, may regulate tumorigenesis (7). Mechanistically, under enriched environments, increased brain-derived neurotrophic factor (BDNF) in the hypothalamus activates β-adrenergic signaling in adipocytes of white adipose tissues, which subsequently lowers circulating adipokine leptin and decreases tumor growth (7). Paradoxically, catecholamine hormones seem to exert contradictory effects in cancer, potentially influenced by the type and intensity of stressors (physical or psychosocial) or the nature and adaptability of biological pathways (8). So far, chronic restraint stress, defined as a distressful circumstance or hostile environment, leads to tumor growth and progression through activation of the sympatho-adrenal system or the HPA axis. In this particular context, adaptability of the pathways was possibly compromised by being overloaded with distress (8). Conversely, enrichment, considered as an eustressful environment, induces a significant inhibition of tumor growth, driven by a possibly more adaptive hypothalamic biological pathway (7). Further in-depth studies would be required to define whether and how distress and eustress can hijack distinct or similar biological pathways leading to different outcomes and to identify underlying molecular mediators or secondary effectors that could trigger opposite effects induced by an identical stress hormone.
The brain processes multiple sensory nerve inputs to provide an adaptive response that prevents any physiologic deviation or restores body homeostasis. Psychologic stressors compromise homeostasis, and thus challenge brain pathways that ultimately affect physiologic systems in the periphery such as the immune system (9). Cancer Research in 2010 highlighted an intriguing study focused on how immune cells within primary tumors respond to psychologic stressors to enhance metastasis, and this study has paved the way for future promising works on psychoneuroimmunology at the interface of cancer research with studies in immunology, neuroscience, psychiatry, and psychology. Beyond stress pathways, cancer can hijack the peripheral and central nervous systems, and is able to build an intratumor autonomic and sensory nerve network embedded in a bidirectional brain–tumor axis (10). Evidence is now emerging that brain regions and populations of neurons can influence at distance tumor behavior. In turn, tumors might regulate brain activities by secreting proinflammatory cytokines, neurotrophic factors or through sensory innervation that signals back to the brain. To further advance research in cancer, a better global understanding of the systemic tumor immune landscape and its regulation by the peripheral and central nervous systems is essential and could present opportunity to unveil pivotal cell partnerships and pathways involved in tumorigenesis and metastasis.
Authors' Disclosures
No disclosures were reported.