Tumor‐associated macrophages (TAMs) promote tumor growth and metastasis by suppressing tumor immune surveillance. Herein, we provide evidence that the immunosuppressive phenotype of TAMs is controlled by long‐chain fatty acid metabolism, specifically unsaturated fatty acids, here exemplified by oleate. Consequently, en‐route enriched lipid droplets were identified as essential organelles, which represent effective targets for chemical inhibitors to block in vitro polarization of TAMs and tumor growth in vivo. In line, analysis of human tumors revealed that myeloid cells infiltrating colon cancer but not gastric cancer tissue indeed accumulate lipid droplets. Mechanistically, our data indicate that oleate‐induced polarization of myeloid cells depends on the mammalian target of the rapamycin pathway. Thus, our findings reveal an alternative therapeutic strategy by targeting the pro‐tumoral myeloid cells on a metabolic level.
Concepts of MetastasisIn 1889, the English surgeon Stephen Paget illustrated his theory on metastasis with the sentence 'When a plant goes to seed, its seeds are carried in all directions, but they can only live and grow if they fall on congenial soil'. He based this 'seed and soil' hypothesis on autopsy records where he detected a discrepancy between the blood supply and frequency of metastasis in specific organs. He concluded that the development of metastasis depends on distinctive features of the tumor cells as well as the specific target organs [1,2]. This concept replaced the mechanistic hypothesis of Rudolf Virchow who considered metastasis as the arrest of tumor cell emboli in the vasculature [2]. Nowadays, metastasis is understood as a complex process of molecular and biochemical events performed by multiple actors. The concept of a 'homogenous seed' has been replaced by a heterogeneous hierarchically organized system of tumorigenic cancer stem cells and their non-tumorigenic progeny [3]. Cancer stem cells are now regarded to be the major driver in metastasis development. In addition, the idea of a sequential development of a cancer from a single primary tumor to the subsequent spread to distant sites was abandoned in the last years and replaced by a model of a simultaneous progression towards metastatic tumor disease. The currently favored model describes the evolution of systemic tumor disease as a parallel development of primary tumor and distant metastasis caused by heterogeneous tumor subpopulations [4].To understand the cellular and molecular basis of metastasis, the most acknowledged approach is the concept of the invasionmetastasis cascade proposed by Isaiah J. Fidler in 2003 and subsequently adapted by Scott Valastyan in 2011 [5,6]. The authors distinguish 6 steps in the process from primary local tumor to distant Keywords Metastasis · Molecular mechanism · Cancer therapy Summary Background:The formation of distant metastases constitutes a complex process with a variety of different genes and pathways involved. To improve patient survival, it is necessary to understand the underlying mechanisms of metastasis to allow for targeted intervention. Methods: This review provides an overview of the general concepts of metastasis, focusing on the most important genes and pathways involved and on interventional strategies. Results: Cancer cells undergo different steps to form metastasis: most prominently, local invasion, intravasation, survival in the circulation, arrest at a distant organ site and extravasation, micrometastasis formation, and metastatic colonization. In order to pass these steps, different molecular pathways are of major importance: EGF/RAS/ RAF/MEK/ERK, PI3K/Akt/mTOR, HGF/Met, Wnt/ -catenin, and VEGF signaling. The HGF/Met regulator MACC1 and the Wnt signaling target S100A4 have been shown to play a major role in the metastatic process. Each gene and pathway provides an opportunity for therapeutic intervention. Conclusion: Since metastasis represents a highly limiting factor in cancer...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.