Abstract
Obesity is a dramatically increasing public health problem worldwide. Traditionally, fat tissue was considered to be solely an energy storage depot. However, recent studies have shown that ...adipose tissue exerts important endocrine functions, which are predominantly mediated by a network of various soluble factors derived from adipocytes. New evidence has come to light elucidating a modulatory role of this adipocytokines in the regulation of cancer development. The most prominent adipocytokines are leptin and adiponectin, which are predominantly secreted by differentiated adipocytes. Depending on the energy status of adipocytes, the secreted concentrations of leptin and adiponectin vary drastically. In obesity, serum level of leptin is considerable increased (greater than or equal to 100 nanogram/ml), whereas the adiponectin concentration is very low. In contrast, adiponectin concentration accelerates by weight reduction (greater than or equal to 10 microgram/ml). The aim of our study was to investigate the influence of adipocytokines on cancer cells. Using our three-dimensional, collagen-based migration assay we found a strong impact of leptin and adiponectin on the migration of colon cancer cells. Both adipocytokines alone significantly enhanced the migratory activity of SW480 colon carcinoma cells from 30.3±7.4% spontaneously locomoting cells to 50.9±8.2%. In contrast, both adipocytokines in combination reduced the migration of colon carcinoma cells to control level. Moreover, treatment of the cells with leptin alone enhanced the proliferation of SW480 cells up to 50%, whereas adiponectin mediated an anti-proliferative function by 30%. Surprisingly, addition of leptin and adiponectin together did not have any effect on the proliferation. On the molecular level, leptin-induced migration was mediated by phosphorylation of focal adhesion kinase (FAK) and activation of phosphatidyl-inositol-3-kinase (PI3K). The pro-migratory effect of adiponectin was accompanied by an activation of PI3K/AKT and various transcription factors. In contrast, incubation with both adipocytokines in combination led to a decreased phosphorylation of FAK and AKT. Understanding the impact of leptin and adiponectin alone and their interplay on the carcinogenesis of colon cancer as well as the underlying molecular mechanisms have a major clinical significance, and provide the basis for the development of novel therapeutics to treat obesity-associated colorectal cancer.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5187.
The protein kinase C (PKC) is a family of serine/threonine kinases that are key regulatory enzymes involved in growth, differentiation, cytoskeletal reorganization, tumor promotion, and migration. We ...investigated the functional involvement of PKC isotypes and of E-cadherin in the regulation of the locomotion of six human colon-adenocarcinoma cell lines. The different levels of the PKC alpha and the E-cadherin expression have predictable implications in the spontaneous locomotory activity. With the use of PKC alpha--specific inhibitors (safingol, Go6976) as well as the PKC delta--specific inhibitor rottlerin, we showed that only PKC alpha plays a major role in the regulation of tumor cell migration. The results were verified by knocking out the translation of PKC isozymes with the use of an antisense oligonucleotide strategy. After stimulation with phorbol ester we observed a translocation and a colocalization of the activated PKC alpha at the plasma membrane to the surrounding extracellular matrix. Furthermore, we investigated the functional involvement of E-cadherin in the locomotion with the use of a blocking antibody. A high level of PKC alpha expression together with a low E-cadherin expression was strongly related to a high migratory activity of the colon carcinoma cells. This correlation was independent of the differentiation grade of the tumor cell lines.
Tumor cells act upon, and react to both their proximate and more distant environment, the mechanisms by which this is achieved being both autocrine and paracrine in nature. This interaction, however, ...takes place not only between adjacent malignant cells, but also non-malignant cells such as those of the immune system, the latter also partaking in the modeling of the tumor environment. Although tumor cells descend from normal tissue cells and thus bear in classical immunological terms 'self signals', it is evident that the immune system is able to recognize tumor cells as a harassment for the body and in consequence tries to eliminate these cells. On the counterpart, tumor cells acquire various characteristics which allow them to evade this immunological surveillance, and have been collectively coined with the term "tumor escape mechanisms". This review will describe and summarize current understanding of tumor escape strategies, and also more closely elaborate on the modulatory role of the neuroendocrine system in the immune system-tumor cell interaction.
Malignant tumors frequently release angiogenic factors, which lead to the vascularization of the tumor, a process called neoangiogenesis. This neoangiogenesis provides sufficient nourishment of the ...tumor when it exceeds a certain size. Recently, a similar mechanism has been postulated for the development of new lymph vessels in tumors, termed lymphangiogenesis. Thus, tumors get access to the circulation and lymph drainage like any other growing or regenerating tissue. Furthermore, it has been hypothesized that neoangiogenesis and lymphangiogenesis support metastasis development. Elaborating on this model, we herein present strong arguments for the new theory that tumors initiate their own innervation by the release of neurotrophic factors in analogy to lymphangiogenesis and neoangiogenesis. For this process, we coin the term neoneurogenesis. It is likely that neoneurogenesis further supports the formation of metastases, since the ingrown nerve endings can release neurotransmitters which enhance the metastasis development. Strikingly, the presence of nerve cell markers in tumor tissues has been shown to be a prognostic marker for the course of a cancer disease, and we have recently reported on the metastasis-increasing function of the neurotransmitter norepinephrine in a mouse model.
Metastasis development requires the migratory activity of tumor cells. It is therefore important to understand the molecular mechanisms of this migration in order to prevent metastasis development, ...which is the pernicious step in most solid tumor diseases. A lot of methods have been invented to investigate tumor cell migration, but not all are equally suited and no method alone is able to deliver a complete picture of tumor cell migration. We herein suggest a combination of three-dimensional in vitro and in vivo methods for the investigation of tumor cell migration and summarize the knowledge, which has been reached so far.
Although great strides have recently been made in elucidating the factors initiating tumor cell migration and the relevant cellular pathways involved, the constituent components of migratory dynamics ...for individual tumor cell motion have still not been resolved. Utilizing a three-dimensional (3D) collagen assay and computer-assisted, continuous single cell tracking, we investigated the basic parameters for both the spontaneous and norepinephrine-induced migration of highly metastatic MBA-MB-468 breast, PC-3 prostate, and SW 480 colon carcinoma cells. We show that tumor cells do not migrate with uniform migrational structure and speed as previously thought, but rather, the induction of locomotion elicits significant increases in speed, break frequency, and total cell displacement, but decreases in break length and no change in the recruitment of nonlocomotory cells. We furthermore illustrate the corresponding morphological changes of induced tumor cell migration with emphasis on motion in a collagen matrix. These results demonstrate the complexity of tumor cell migration, and the compulsion for incorporating not only knowledge of intracellular pathways, but also fundamental parameters of migratory behavior into any expansive theory of tumor cell migration and metastasis formation. We furthermore establish the analytical methodology of investigating both the stimulation and potential pharmaceutical inhibition of tumor cell migration.
Natural killer (NK) cells and cytotoxic T lymphocytes (CTL), the functional coordination of which are governed by various signal substances, are crucial in the body’s defense of tumor and ...virus-infected cells. We investigated the role of various neurotransmitters and hormones on the regulation of functional parameters, including NK cell cytotoxicity, and the migration of NK cells and CTL within a three-dimensional collagen lattice. Using peripheral blood CTL and NK cells, we show that the neurotransmitters endorphin, histamine and substance P increase NK cell cytotoxicity, while norepinephrine inhibits cytotoxicity. Moreover, substance P reduces migratory activity, while norepinephrine increases NK cell and CTL migration. Furthermore, all three steroid hormones which were investigated, namely cortisone, testosterone, and estradiol, had regulatory influence on both cytotoxicity and migration of NK cells. These results further specify the functional basis of the complex interconnection between the immune and neuro-endocrine systems.
Neurotransmitters are signal substances that have traditionally been regarded as mere mediators of signal states between cells in the nervous system. Whereas the mechanisms of this "classic" ...neurotransmitter regulation are well understood, only recently has new evidence come to light elucidating the modulatory role of neurotransmitters in immune function, and in the regulation of migration of leukocytes and tumor cells. The migration of leukocytes is, among other things, of primary importance for an anti-tumor immune response, whereas the migration of tumor cells is a prerequisite for invasion and the development of metastases. We here clarify and consolidate the latest tumor biological findings on the role of these neurotransmitters, which bind to serpentine receptors, and which are involved in leukocyte migration, tumor growth, invasion and metastasis. This review thus accentuates the complex, interactive involvement of neurotransmitters in the regulation of migration of both leukocytes and tumor cells.
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