The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues

Abstract

Despite advancements in cancer management, tumor relapse and metastasis are associated with poor outcomes in many cancers. Over the past decade, oncogene-driven carcinogenesis, dysregulated cellular signaling networks, dynamic changes in the tissue microenvironment, epithelial-mesenchymal transitions, protein expression within regulatory pathways, and their part in tumor progression are described in several studies. However, the complexity of metabolic enzyme expression is considerably under evaluated. Alterations in cellular metabolism determine the individual phenotype and behavior of cells, which is a well-recognized hallmark of cancer progression, especially in the adaptation mechanisms underlying therapy resistance. In metabolic symbiosis, cells compete, communicate, and even feed each other, supervised by tumor cells. Metabolic reprogramming forms a unique fingerprint for each tumor tissue, depending on the cellular content and genetic, epigenetic, and microenvironmental alterations of the developing cancer. Based on its sensing and effector functions, the mechanistic target of rapamycin (mTOR) kinase is considered the master regulator of metabolic adaptation. Moreover, mTOR kinase hyperactivity is associated with poor prognosis in various tumor types. In situ metabolic phenotyping in recent studies highlights the importance of metabolic plasticity, mTOR hyperactivity, and their role in tumor progression. In this review, we update recent developments in metabolic phenotyping of the cancer ecosystem, metabolic symbiosis, and plasticity which could provide new research directions in tumor biology. In addition, we suggest pathomorphological and analytical studies relating to metabolic alterations, mTOR activity, and their associations which are necessary to improve understanding of tumor heterogeneity and expand the therapeutic management of cancer.

Nasopharyngeal carcinoma ecology theory: cancer as multidimensional spatiotemporal “unity of ecology and evolution” pathological ecosystem

“…It has been proved that both of mechanical tissue stiffness and metabolic modulation affect directly each other to cause genome-wide changes in epigenetic regulatory states. ECM acts as a metabolic niche in tissue microenvironment, and its targeted therapeutic management might cause metabolic rewiring of tumor cells, and influence crosstalk between nonmalignant and malignant cell phenotypes in the metabolic ecosystem 196 . As far as I know, it is the first time to introduce the mulberry-fish-ponds model to the area of cancer ecology.…”

Extracellular Vesicle-Mediated Metastasis Suppressors NME1 and NME2 Modify Lipid Metabolism in Fibroblasts

“…Cancer cells were also shown to induce metabolic changes in stromal cells; these changes allow CAFs to display activities, which support growth and progression of cancer cells. Metabolic adaptation is recognised as a hallmark of cancer [ 38 ]: crosstalk of cancer cells and cells forming the tumour microenvironment results in a metabolic symbiosis during tumour progression [ 54 ]. For example, in an orthotopic mouse model for ovarian carcinoma, glutamine supply of cancer cells was ensured by cancer-associated fibroblasts [ 55 ].…”

The role of angiogenesis in melanoma: Clinical treatments and future expectations

“…For instance, several studies have shown vessel co-option is associated with primary melanoma and organ (brain, lung, and liver) metastases of melanoma (Lugassy et al, 2014;Szabo et al, 2015;Bentolila et al, 2016;Barnhill et al, 2018;Rodewald et al, 2019), which may be an essential factor for poor clinical effectiveness of anti-angiogenic drugs. Secondly, in terms of the resistance mechanism to anti-angiogenic therapy, metabolic symbiosis is also reported in both experimental and clinical studies (Jimenez-Valerio et al, 2016;Sebestyen et al, 2021). Both OXPHOS and glycolysis (metabolic symbiosis) have been identified to be critical for metabolic plasticity in melanoma, driving acquired resistance to anti-angiogenic chemotherapy (Kumar et al, 2021).…”