The Many Facets of Tumor Heterogeneity: Is Metabolism Lagging Behind?

Abstract

Tumor functional heterogeneity has been recognized for decades, and technological advancements are fueling renewed interest in uncovering the cell-intrinsic and extrinsic factors that influence tumor development and therapeutic response. Intratumoral heterogeneity is now arguably one of the most-studied topics in tumor biology, leading to the discovery of new paradigms and reinterpretation of old ones, as we aim to understand the profound implications that genomic, epigenomic, and functional heterogeneity hold with regard to clinical outcomes. In spite of our improved understanding of the biological complexity of cancer, characterization of tumor metabolic heterogeneity has lagged behind, lost in a century-old controversy debating whether glycolysis or mitochondrial respiration is more influential. But is tumor metabolism really so simple? Here, we review historical and current views of intratumoral heterogeneity, with an emphasis on summarizing the emerging data that begin to illuminate just how vast the spectrum of metabolic strategies a tumor can employ may be, and what this means for how we might interpret other tumor characteristics, such as mutational landscape, contribution of microenvironmental influences, and treatment resistance.

Metabolic Constrains Rule Metastasis Progression

“…Similarly, multiple cancers have been shown to be metabolically heterogeneous, with a distinct part of tumoral tissue activating distinct metabolic pathways. In this way, cancer cells dynamically adapt to and cope with the surrounding microenvironment where nutrient and oxygen shortage imposes the activation of and the addiction to specific metabolic pathways [102]. Then, tumor metabolism is spatially dictated by the interaction with the surrounding microenvironment, where cancer associated fibroblasts, blood vessels, and immune cells are heterogeneously distributed [103,104].…”

Gene Therapy in Cancer Treatment: Why Go Nano?

“…According to the World Health Organization, cancer is the second leading cause of death worldwide, accounting for 9.6 million deaths in 2018 [1]. The global efforts in cancer prevention, early diagnosis, screening and treatment, have been challenged by the complexity and variability of tumors (reviewed in [2]). The genomic instability of tumor cells and a pro-inflammatory environment are key factors for tumor growth [3].…”

“…The genomic instability of tumor cells and a pro-inflammatory environment are key factors for tumor growth [3]. Regardless of the monoclonal origin of the neoplasia, the interplay between tumor cells and the surrounding environment results in a complex tumor microenvironment (TME) that supports tumor intra-heterogeneity, with spatially different and phenotypically distinct subclones [2]. Nonetheless, major common features of tumor cells include continuous proliferative signaling, evasion of growth suppressors, resisting cell death, replicative immortality, deregulating cellular energetics, promoting angiogenesis, activating invasion and metastasis, and avoiding immune destruction [3].…”

Neural signaling modulates metabolism of gastric cancer

“…tumor microenvironment (TME) that usually is different from normal stroma. As cancer cells continue proliferation, the tumor increases in size with an associated remodeling of the TME that determines whether the primary tumor is eradicated, metastasizes, or establishes dormant micrometastases ( Loponte et al., 2019 ; Yoshida, 2015 ; Vander Heiden and Deberardinis, 2017 ). The cancer metabolic reprogramming is reflected by alterations in the metabolic profiles of both cancer cells as well as TME.…”