Metastatic disease is the primary cause of death for most cancer patients. Complex and redundant pathways involving the tumor cell and the microenvironment mediate tumor invasion at the primary site, survival and arrest in the bloodstream, and progressive outgrowth at a distant site. Understanding these pathways and their dynamic interactions will help identify promising molecular targets for cancer therapy and key obstacles to their clinical development.

Tumor metastasis: mechanistic insights and clinical challenges

Little is known about how the genotypic and molecular abnormalities associated with epithelial cancers actually contribute to the histological phenotypes observed in tumours in vivo. 3D epithelial culture systems are a valuable tool for modelling cancer genes and pathways in a structurally appropriate context. Here, we review the important features of epithelial structures grown in 3D basement membrane cultures, and how such models have been used to investigate the mechanisms associated with tumour initiation and progression.

Modelling glandular epithelial cancers in three-dimensional cultures.

Tumorigenesis is a complex and dynamic process, consisting of three stages: initiation, progression, and metastasis. Tumors are encircled by extracellular matrix (ECM) and stromal cells, and the physiological state of the tumor microenvironment (TME) is closely connected to every step of tumorigenesis. Evidence suggests that the vital components of the TME are fibroblasts and myofibroblasts, neuroendocrine cells, adipose cells, immune and inflammatory cells, the blood and lymphatic vascular networks, and ECM. This manuscript, based on the current studies of the TME, offers a more comprehensive overview of the primary functions of each component of the TME in cancer initiation, progression, and invasion. The manuscript also includes primary therapeutic targeting markers for each player, which may be helpful in treating tumors.

/pdf/role-of-tumor-microenvironment-in-tumorigenesis-4qz05m460a.pdf

Role of tumor microenvironment in tumorigenesis.

The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal routes. The neuroendocrine stress response and the sympathetic and parasympathetic nervous systems generally inhibit innate immune responses at systemic and regional levels, whereas the peripheral nervous system tends to amplify local innate immune responses. These systems work together to first activate and amplify local inflammatory responses that contain or eliminate invading pathogens, and subsequently to terminate inflammation and restore host homeostasis. Here, I review these regulatory mechanisms and discuss the evidence indicating that the CNS can be considered as integral to acute-phase inflammatory responses to pathogens as the innate immune system.

/pdf/neural-regulation-of-innate-immunity-a-coordinated-17ihqcyui3.pdf

Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens

Stress does not cause cancer per se, but depression and a lack of social support might influence cancer progression and clinical outcome. Can identification of the molecular and biological mechanisms involved be used to improve patient treatment? Epidemiological studies indicate that stress, chronic depression and lack of social support might serve as risk factors for cancer development and progression. Recent cellular and molecular studies have identified biological processes that could potentially mediate such effects. This review integrates clinical, cellular and molecular studies to provide a mechanistic understanding of the interface between biological and behavioural influences in cancer, and identifies novel behavioural or pharmacological interventions that might help improve cancer outcomes.

/pdf/the-influence-of-bio-behavioural-factors-on-tumour-biology-144zmhhl5z.pdf

The influence of bio-behavioural factors on tumour biology: pathways and mechanisms

The development of metastases is a decisive step in the course of a cancer disease. The detection of metastases in cancer patients is correlated with a poor prognosis, and over 90% of all deaths from cancer are not due to the primary tumor, which often can be successfully treated, but are due to the metastases. Tumor cell migration, a prerequisite for metastasis development, is not merely genetically determined, but is distinctly regulated by signal substances of the environment including chemokines and neurotransmitters. We have shown previously that the migration of breast, prostate, and colon carcinoma cells is enhanced by the stress-related neurotransmitter norepinephrine in vitro, and that this effect can be inhibited by the beta-blocker propranolol. We now provide for the first time evidence for the in vivo relevance of this neurotransmitter-driven regulation using PC-3 prostate carcinoma cells. The development of lumbar lymph node metastases in athymic BALB/c nude mice increased with the application of norepinephrine via microosmotic pumps, while propranolol inhibited this effect. However, the growth of the primary tumor was not affected by either treatment. Additionally, experiments using human tissue microarrays showed that 70-90 percent of breast, colon, and prostate carcinoma tissues express the relevant beta2-adrenoceptor. Thus, our work contributes to the understanding of the basic cellular mechanisms of metastasis development, and furthermore delivers a rationale for the chemopreventive use of clinically established beta-blockers for the inhibition of metastases.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.21723

The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by β-blockers

Summary Cancer starts as a localised disease, which, if detected early, can often be treated successfully by removal of the primary tumour. A pernicious progression is the invasion of tumour cells into surrounding tissues, resulting in development of distant metastases. Because active migration of tumour cells is a prerequisite for tumour-cell invasion and metastasis, a pressing goal in tumour biology has been the elucidation of factors regulating the migratory activity of these cells. The most prominent regulatory factors are ligands to serpentine receptors—eg, chemokines and neurotransmitters. Many types of neurotransmitter receptors are expressed on tumour cells, supporting the theory that psychosocial factors are involved in the progression of cancer. Understanding how such receptors regulate migration and the availability of specific receptor antagonists could open up new avenues for chemoprevention of tumour-cell migration and metastatic development.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470204504014317.pdf

Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters.

Most patients suffering from breast carcinoma do not die due to the primary tumor but from the development of metastases. Active migration of cancer cells is a prerequisite for development of these metastases. We used time-lapse videomicroscopy and computer-assisted cell tracking of MDA-MB-468 human breast carcinoma cells, which were incorporated into a three-dimensional collagen matrix, in order to analyze the migratory activity of these cells in response to different neurotransmitters. Our results show that met-enkephalin, substance P, bombesin, dopamine, and norepinephrine have a stimulatory effect on the migration of the breast cancer cells; moreover, these cells show positive chemotaxis towards norepinephrine as was analyzed by the directionality and persistence on a single-cell basis. Gamma-aminobutyric acid (GABA) however has an inhibitory effect. Endorphin and leu-enkephalin, as well as histamin and acetylcholine, had no influence on the migratory activity of the cells. In summary, we provide evidence for a strong regulatory involvement of neurotransmitters in the regulation of breast cancer cell migration, which might provide the basis for the use of the pharmacological agonists and antagonists for the chemopreventive inhibition of metastasis development.

Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells.

Cancer starts as a localised disease, which, if detected early, can often be treated successfully by removal of the primary tumour. A pernicious progression is the invasion of tumour cells into surrounding tissues, resulting in development of distant metastases. Because active migration of tumour cells is a prerequisite for tumour-cell invasion and metastasis, a pressing goal in tumour biology has been the elucidation of factors regulating the migratory activity of these cells. The most prominent regulatory factors are ligands to serpentine receptors-eg, chemokines and neurotransmitters. Many types of neurotransmitter receptors are expressed on tumour cells, supporting the theory that psychosocial factors are involved in the progression of cancer. Understanding how such receptors regulate migration and the availability of specific receptor antagonists could open up new avenues for chemoprevention of tumour-cell migration and metastatic development.

Iconography : Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters

The active migration of tumor cells, a crucial requirement for metastasis development and cancer progression, is regulated by signal substances including neurotransmitters. We investigated the migration of tumor cells within a three-dimensional collagen matrix using time-lapse videomicroscopy and computer-assisted analysis of the migration path. Tumor cell migration is induced by norepinephrine, dopamine and substance P. We show that this induced migration, using MDA-MB-468 breast and PC-3 prostate carcinoma cells, can be inhibited by using specific, clinically established receptor antagonists to the beta2-adrenoceptor, the D2 receptor, or the neurokinin-1 receptor, respectively. All of the investigated neurotransmitters significantly activated the cyclic adenosine-monophosphate response element binding protein (CREB). Furthermore, microarray analysis revealed changes of gene expression toward a highly motile tumor cell type, including an upregulation of the alpha2 integrin, which is an essential adhesion receptor for collagen in migration. The gene for the tumor suppressor gelsolin was downregulated. These 2 critical alterations were confirmed on the protein level by flow-cytometry and immunoblotting, respectively. Neurotransmitters thus induce a metastatogenic tumor cell type by directly regulating gene expression and increased migratory activity, which can be prevented by established neurotransmitter antagonists.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.20410

Theodore L. Drell

Papers

The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by β-blockers

Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters.

Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells.

Iconography : Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters

Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs.