Metabolic Constrains Rule Metastasis Progression

Abstract

Metastasis formation accounts for the majority of tumor-associated deaths and consists of different steps, each of them being characterized by a distinctive adaptive phenotype of the cancer cells. Metabolic reprogramming represents one of the main adaptive phenotypes exploited by cancer cells during all the main steps of tumor and metastatic progression. In particular, the metabolism of cancer cells evolves profoundly through all the main phases of metastasis formation, namely the metastatic dissemination, the metastatic colonization of distant organs, the metastatic dormancy, and ultimately the outgrowth into macroscopic lesions. However, the metabolic reprogramming of metastasizing cancer cells has only recently become the subject of intense study. From a clinical point of view, the latter steps of the metastatic process are very important, because patients often undergo surgical removal of the primary tumor when cancer cells have already left the primary tumor site, even though distant metastases are not clinically detectable yet. In this scenario, to precisely elucidate if and how metabolic reprogramming drives acquisition of cancer-specific adaptive phenotypes might pave the way to new therapeutic strategies by combining chemotherapy with metabolic drugs for better cancer eradication. In this review we discuss the latest evidence that claim the importance of metabolic adaptation for cancer progression.

Beyond Genetics: Metastasis as an Adaptive Response in Breast Cancer

“…The “cell-of-origin” then undergoes clonal expansion, a process that is accompanied by the acquisition of further genetic and phenotypic traits, thereby generating a state of Intra-Tumor Heterogeneity (ITH; [ 118 ]). As a consequence, breast tumors, though clonal in origin, become polyclonal systems [ 119 , 120 ], whereby different clones (i.e., populations of cells that originate from a common ancestor) differ in terms of their genomic and phenotypic profiles [ 121 , 122 , 123 ].…”

“…The deregulated growth of primary breast tumors is associated with the exhaustion of the local nutrient microenvironment, which leads to progressive nutrient deprivation, the accumulation of waste products and metabolic stress [ 123 ]. A pivotal study on transformed mammary cells revealed that glutamine deprivation strongly fosters the expression of stress-response genes (e.g., ATF4, DDIT3 and XBP1), including inflammatory mediators (e.g., KLF4, CCL2, NF-κB1 and IL20) and it increases the migratory phenotype of tumor cells [ 188 ].…”

Cancer Metabolism as a New Real Target in Tumor Therapy

“…Metastatic progression is based on the ability of cancer cells to acquire an adaptive phenotype disseminating to distant organ sites and evading the immune system. In this context, two comprehensive reviews, proposed by Roda and colleagues [37] and by Benzarti and colleagues [38], examined complementary features of this critical matter, pointing out the ability of cancer cells to gain a bioenergetic shift and discussing the role of metabolic reprogramming in eliciting the metastatization process.…”

Blood Vessels and Peripheral Nerves as Key Players in Cancer Progression and Therapy Resistance

“…Tumorigenesis represents a dynamic process that induces normal cells to lose their own specific identity and to acquire a series of malignant traits, including deregulated proliferation, evasion of apoptosis and immunosurveillance, and abnormal metabolism [1][2][3]. Notably, this process is driven by two main factors, namely, tumor-specific mutational burden, on one hand, and the continuous interaction of cancer cells with the surrounding stroma, on the other hand [4,5].…”