Theodore L. Drell

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

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 β‐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 β2‐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 β‐blockers for the inhibition of metastases.

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

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.

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

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 β2‐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 α2 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.

Stem Cell Migration: A Quintessential Stepping Stone to Successful Therapy

Migration is an innate and fundamental cellular function that enables hematopoietic stem cells (HSCs) and endothelial progenitors (EPCs) to leave the bone marrow, relocate to distant tissue, and to return to the bone marrow. An increasing number of studies demonstrate the widening scope of the therapeutic potential of both HSCs and endothelial cells. Therapeutic success however not only relies upon their ability to repair damaged tissue, but is also fundamentally dependent on the migration to these areas. Extensive in vivo and in vitro research efforts have shown that the most significant effects seen on HSC migration are initiated by the chemokine SDF-1alpha. In this review we will elucidate the many cellular and systemic factors of HSC and EPC cell migration and their modi operandi.

Neurotransmitters and chemokines regulate tumor cell migration: potential for a new pharmacological approach to inhibit invasion and metastasis development.

The migration of tumor cells is a prerequisite for tumor cell invasion and metastasis development, which accounts for over 90% of cancer mortality. Therefore a major focus of current tumor biological research is the study of those factors that regulate tumor cell migration. Those chemokines and neurotransmitters that bind to G-protein coupled receptors (also known as serpentine receptors) are the most prominent of these factors. Neurotransmitters have been identified that have not only a stimulatory (e.g. norepinephrine) effect, but an inhibitory effect (e.g. GABA) as well. This is an especially fortuitous development, because many known agonists and antagonists of neurotransmitter receptors are currently being successfully used in the treatment of other pathological conditions (e.g. beta-blockers in the treatment of cardiovascular diseases). Likewise, chemokine receptor antagonists, which are under development for the treatment of HIV or rheumatoid arthritis, may be effective tools for the inhibition of chemokine-driven tumor cell migration as well. A further approach to inhibit tumor cell migration arises from the investigation of the relevant signal transduction pathways. The PKC alpha, for example, is a key enzyme in the regulation of tumor cell migration, but not of leukocyte migration. It thus offers a selective target opportunity for specific pharmacological agents to interfere with tumor cell migration. In this review we therefore summarize the current findings on those serpentine receptors involved in the neurotransmitter- and chemokine-regulated tumor cell migration, on the underlying signal transduction pathways, and on the opportunities to inhibit tumor cell migration and ultimately metastasis development with pharmaceutical agents.

Inhibitors for Metastasis Development

A leading cause of death, cancer remains the bane of modern society and one of the most challenging research fields. Cancer is initially a localized disease that can be often treated well at a very early stage. However the vast majority of cancer deaths result from a pernicious progression of the disease, the development of distant metastases. It must therefore be a pressing research goal to focus on the pharmacological prevention of metastasis development. This review summarizes the current understanding of the cellular and molecular mechanisms of metastasis development, and suggests possible approaches for its inhibition.

Translational Research in Oncology: The Need of Additional In Vitro Preclinical Testing Methods for New Drugs

Cancer remains one of the leading causes of death in the Western world. Despite bold advances in therapeutic oncology, new drug development is infamously ineffective due to the lack of predictive in vitro models. Most patients that suffer from cancer do not die from the primary tumor but due to the development of metastases. And yet current in vitro screening methods for new drugs in oncology still largely target cytotoxicity or the inhibition of cell growth, in which a potential anti-metastatic activity cannot be assessed. Herein the current in vitro models in oncology are reviewed and a new rationale for the pre-clinical development of specific, anti-metastatic therapeutic agents is introduced.