Tumor macroenvironment and metabolism

Abstract

In this review we introduce the concept of the tumor macroenvironment and explore it in the context of metabolism. Tumor cells interact with the tumor microenvironment including immune cells. Blood and lymph vessels are the critical components that deliver nutrients to the tumor and also connect the tumor to the macroenvironment. Several factors are then released from the tumor itself but potentially also from the tumor microenvironment, influencing the metabolism of distant tissues and organs. Amino acids, and distinct lipid and lipoprotein species can be essential for further tumor growth. The role of glucose in tumor metabolism has been studied extensively. Cancer-associated cachexia is the most important tumor-associated systemic syndrome and not only affects the quality of life of patients with various malignancies but is estimated to be the cause of death in 15%-20% of all cancer patients. On the other hand, systemic metabolic diseases such as obesity and diabetes are known to influence tumor development. Furthermore, the clinical implications of the tumor macroenvironment are explored in the context of the patient's outcome with special consideration for pediatric tumors. Finally, ways to target the tumor macroenvironment that will provide new approaches for therapeutic concepts are described.

Figure 1

The tumor macroenvironment concept. A simplified schematic of the tumor micro- and macroenvironment: tumor development is a multi-step process that may take place over several years. Transition from normal cell(s) to genetically abnormal cell(s) occurs at the beginning. This transition is a relatively slow process and often clinically silent. When transformed cells start dividing and invade the neighboring tissues, the tumor microenvironment evolves. At this step, cancer cells may face destructive effects of the innate and adaptive immune systems. However, selected cancer cells are able to escape the antitumor immune response, resume growth, proliferate and shape their microenvironment. Importantly, the reciprocal—but abnormal—interactions between cancer cells and the surrounding tissue are mainly localized and limited to the microenvironment at this stage (left). If cancer cells remain undetected and untreated, cancer progresses to advanced stages. As a consequence of (1) abnormal localized interaction and (2) uncontrolled cancer cell proliferation and resulting necrosis, several soluble factors are released from the tumor microenvironment. They may function as proangiogenic factors that stimulate recruitment of endothelial progenitor cells to the tumor microenvironment and induce angiogenesis. Tumor-induced angiogenesis is a critical process in tumor development, as it not only supplies the tumor with required nutrients but also allows soluble factors released by the tumor and the microenvironment to enter the blood and/or lymph stream. This leads to an increased complexity of systemic interactions between the tumor and other organs and systems in the body. In contrast to the tumor microenvironment, where the localized auto and paracrine types of interaction are dominating, the systemic pathological interactions constitute the fundamental mechanism of the tumor macroenvironment concept in cancer biology (right).