Abstract
Rho GTPases are a family of small G proteins that regulate a wide array of cellular processes related to their key roles controlling the cytoskeleton. Cancer is a multistep disease caused by the accumulation of genetic mutations and epigenetic alterations, from the initial stages of cancer development when cells in normal tissues undergo transformation, to the acquisition of invasive and metastatic traits, responsible for a large number of cancer related deaths. In this review, we discuss the role of Rho GTPase signaling in cancer in every step of disease progression. Rho GTPases contribute to tumor initiation and progression, by regulating proliferation and apoptosis, but also metabolism, senescence, and cancer cell stemness. Rho GTPases play a major role in cell migration and in the metastatic process. They are also involved in interactions with the tumor microenvironment and regulate inflammation, contributing to cancer progression. After years of intensive research, we highlight the importance of relevant models in the Rho GTPase field, and we reflect on the therapeutic opportunities arising for cancer patients.
Highlights
Cancer is a multistep disease caused by the accumulation of genetic mutations and/or epigenetic alterations
Rho GTPases are generally thought to be active when bound to GTP and inactive when bound to GDP, cycling between these two states regulated by two opposing protein families: guanine nucleotide exchange factors (GEFs)
RHO-ROCK-myosin light chain 2 (MLC2) promoted survival of myeloid and leukemia cells bearing oncogenic KIT, FLT3, and BCRABL, leading to development of acute myeloid leukemia (AML) and myeloproliferative disease (MPD) [105]; while inhibiting ROCK function resulted in apoptosis of AML cells [296]
Summary
Cancer is a multistep disease caused by the accumulation of genetic mutations and/or epigenetic alterations. Ability to invade, disseminate, and survive in secondary sites enables metastasis formation, which is responsible for the majority of cancer related deaths. These capabilities, defined as hallmarks of cancer by Hanahan and Weinberg [1], include evasion of immune-surveillance and reprogramming of cellular metabolism, in. Rho GTPase signaling contributes to all hallmarks of cancer and emerges as a novel therapeutic target. We discuss the role of Rho GTPase signaling in cancer, from their involvement in initial stages of carcinogenesis to their role in tumor progression, dissemination, and interaction with the tumor microenvironment (TME)
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