Tumor metabolism: metabolic alterations and heterogeneity in cancer progression

Excerpt

The number of malignant cells even in a small tumor could be extremely high. According to some estimates, there are more cells in a 10-g tumor than humans alive on the planet. The tumor mass, which contains malignant and surrounding non-malignant cells in the tissue microenvironment, is extremely diverse. The importance of intra-tumoral heterogeneity—highlighted as immunophenotype heterogeneity nearly 40 years ago in Cancer and Metastasis Reviews—was introduced by Miller and Heppner [1‐3]. Tumor tissue heterogeneity contributes to the appreciated somatic evolutionary process in cancer development and progression [4, 5]. While the elements (mutations, selections, genetic drifts, fitness, epistasis) of this evolutionary process are weakly described, it is conventionally accepted that selection acts on phenotype rather than genotype, which is mainly deterministic. Eliminating such a complex and often disseminated metastatic population such as cancer is more than challenging. The diversity-served signaling, compensatory and adaptation mechanisms in tumor progression could be the basis of therapeutic failures. Gene-sequencing-centric views have dominated molecular cancer research to date, but among genetic diversity and heterogeneity further factors influence the alterations in the tumor cell population. In the last two decades, several phrases provided understanding of the evolutionary and ecologic alterations in tumor development. In addition to genetic diversity, local and time-dependent tissue heterogeneity, immune regulatory differences, tumor tissue symbiosis, plasticity, and metabolic heterogeneity have gained special attention. Metabolic adaptation, symbiosis, plasticity, and fitness have been used to describe tumor evolution. It is well established that accelerated tumor growth can occur only with sufficient energy, building blocks, and nutrient support. Metabolic flexibility and plasticity are necessary for cancer progression. Environmental adaptation, metabolic activity, and rewiring are critical for maintaining the survival and growth of the tumor population [6‐8]. …