The role of the tumor microenvironment in tumor progression Free

ED03-01

The tumor tissue is composed of 2 compartments intimately associated with each other. The first compartment constitutes the malignant cells. The second is the tumor microenvironment. This compartment is composed of resident cells such as fibroblasts, endothelial cells and other non-malignant cells; of infiltrating cells such as lymphocytes or macrophages and of numerous molecules such as those of the extracellular matrix, growth factors, cytokines, chemokines, antibodies, proteases, other types of enzymes and various metabolites. Cellular products released from necrotic cells (mainly tumor cells) are also present. All these molecules may be released from the tumor cells and/or from the non malignant cells. Some artificially administered molecules, for example drugs, may also be present in the microenvironment. The microenvironment of many solid tumors may be characterized by hypoxia; low extracellular pH and by low glucose concentration.
 Although the term tumor microenvironment is used most often with respect to solid tumors, other types of malignancies have also their specific microenvironments. The bone marrow serving as a microenvironment for certain leukemias and for multiple myeloma is a case in point.
 The contemporary concept of tumor microenvironment postulates that it functions as an active “educational/inductive/selection” venue in which the tumor is directed into one of several molecular evolution pathways by microenvironmental factors. The interaction between microenvironmental components and tumor cells is a two way street. In addition to the regulation of genes in tumor cells by microenvironmental factors, tumor cells and their products are capable of regulating gene expression in non-tumor cells residing in or infiltrating into the microenvironment thereby altering their phenotype.
 There are scores of tumor-microenvironment interactions that play anti or pro malignancy roles. These include interactions that lead to or drive cell proliferation or death, angiogenesis, motility, chemotaxis, invasion, protective immunity, inflammation and metastasis to name a few. Many such interactions await their discovery and the significance of other interactions has still to be elucidated.
 It is now widely accepted that interactions of cancer cells with components of their microenvironment are crucial and pivotal determinants in the decision making process that determines if cancer cells will progress towards metastasis or whether they will stay dormant or disappear altogether.
 The metastatic cascade is initiated when cells from the primary tumor detach and penetrate the extracellular matrix (ECM). Much of this invasive behavior depends upon the secretion of a variety of degrading enzymes, on alterations in the expression of adhesion molecules, on responses to cytokines and chemokines and on gene products regulating motility. A fraction of the invading cells penetrates into the vascular system (intravasation). The tumor cells in the blood form emboli with platelets and leukocytes, adhere to the endothelium of certain organs, extravasate and migrate into secondary sites to form site specific metastasis. Each of these steps involves an interaction between tumor cells and microenvironmental factors.
 Can metastasis be prevented in a tumor bearer? In view of the fact that metastasis is, in many cases, present already when a primary tumor is diagnosed, the straight forward answer to this question is no.
 However, metastasis is a relatively inefficient process that proceeds throughout the tumor-bearer period. It is therefore reasonable to hypothesize that the metastatic process can be halted or at least hindered.
 The realization that metastasis is controlled by interactions of tumor cells with microenvironmental components has allowed for the establishment of a new paradigm, namely intervention in the metastatic process by targeting interactions between the tumor cell and its microenvironment. Numerous preclinical and clinical trials attempt, on the one hand, to block tumor-microenvironment interactions that boost tumor progression and metastasis and on the other hand enhance interactions that counteract malignancy.
 Aiming to develop rational and effective therapy modalities that would interfere with the metastatic cascade, we need to elucidate the molecular and cellular interactions that drive metastasis; identify the anti metastasis interactions operating in the tumor microenvironment and determine the net balance between them. We must also consider the unique properties of the tumor microenvironment. These include an overwhelming complexity of intertwined signaling pathways, an abnormality of its “normal”, non-malignant compartment; opposing effects of some of its components on metastasis and many circular chains of tumor-progression-enhancing events that may be described as vicious cycles.
 In order to develop effective anti metastasis therapies and in view of the complexity of tumor-microenvironment interactions, combinatorial approaches used in the analysis of hyper complex systems will have to be employed.