MYC as a Multifaceted Regulator of Tumor Microenvironment Leading to Metastasis

Abstract

The Myc family of oncogenes is deregulated in many types of cancer, and their over-expression is often correlated with poor prognosis. The Myc family members are transcription factors that can coordinate the expression of thousands of genes. Among them, c-Myc (MYC) is the gene most strongly associated with cancer, and it is the focus of this review. It regulates the expression of genes involved in cell proliferation, growth, differentiation, self-renewal, survival, metabolism, protein synthesis, and apoptosis. More recently, novel studies have shown that MYC plays a role not only in tumor initiation and growth but also has a broader spectrum of functions in tumor progression. MYC contributes to angiogenesis, immune evasion, invasion, and migration, which all lead to distant metastasis. Moreover, MYC is able to promote tumor growth and aggressiveness by recruiting stromal and tumor-infiltrating cells. In this review, we will dissect all of these novel functions and their involvement in the crosstalk between tumor and host, which have demonstrated that MYC is undoubtedly the master regulator of the tumor microenvironment. In sum, a better understanding of MYC's role in the tumor microenvironment and metastasis development is crucial in proposing novel and effective cancer treatment strategies.

Keywords: EMT; MYC; TAMs; metastasis; tumor microenvironment.

Figure 1

The role of MYC in cancer aggressiveness and progression. An increasing number of studies show that, besides the canonical functions such as cell proliferation, growth, differentiation, self-renewal, survival, metabolism, protein synthesis, and apoptosis, MYC is also directly or indirectly involved in other processes necessary for tumor progression—metabolic rewiring, immune evasion, angiogenesis, ExtraCellular Matrix (ECM) remodeling and invasion, migration, Epithelial-to-Mesenchymal Transition (EMT) and metastasis.

Figure 2

MYC and the tumor microenvironment. (A) MYC is an essential instructor of the tumor microenvironment [11,18,24,30,103,104]. MYC promotes cancer aggressiveness not only by influencing cancer cells’ biology but also by recruiting stromal and infiltrating inflammatory cells. The goal of this MYC-regulated crosstalk between host and cancer is to create a microenvironment that is favorable for cancer cells—facilitating growth, invasion, migration, and helping to evade the anti-tumor immune responses. (B) MYC controls the “angiogenic switch” [54,99]. MYC is involved in a lot of different direct and indirect mechanisms for promoting angiogenesis. MYC induces secretion of VEGF both in cancer cells and tumor-associated cells. VEGF proves to be the main factor in promoting MYC-dependent angiogenesis.

Figure 3

MYC is an important player in the formation of metastasis. Metastasis is a complex process involving the detachment from the primary tumor, intravasation into the bloodstream, survival within circulation, arrest, extravasation, and colonization at distant sites. MYC regulates metastasis formation using several different approaches—directly, co-operating with other oncoproteins, epigenetically, using a network of ncRNAs or recruiting components of the microenvironment. EMT seems to be at the center of MYC-induced metastasis [13,24,25,31,112,172,178,179,183,191,242].