Intracellular Transport in Cancer Metabolic Reprogramming

Abstract

Tumor progression is a complex process consisting of several steps characterized by alterations in cellular behavior and morphology. These steps include uncontrolled cell division and proliferation, invasiveness and metastatic ability. Throughout these phases, cancer cells encounter a changing environment and a variety of metabolic stress. To meet their needs for energy while they proliferate and survive in their new environment, tumor cells need to continuously fine-tune their metabolism. The connection between intracellular transport and metabolic reprogramming during cancer progression is emerging as a central process of cellular adaptation to these changes. The trafficking of proteolytic enzymes, surface receptors, but also the regulation of downstream pathways, are all central to cancer progression. In this review, we summarize different hallmarks of cancer with a special focus on the role of intracellular trafficking in cell proliferation, epithelial to mesenchymal transition as well as invasion. We will further emphasize how intracellular trafficking contributes to the regulation of energy consumption and metabolism during these steps of cancer progression.

Keywords: cancer cell metabolism; cell proliferation; epithelial to mesenchymal transition; invasion; membrane trafficking.

FIGURE 1

Overview of nutrient scavenging pathways in cancer cells. During cancer progression, cancer cells increase their energy and nutrient requirement to meet the demand of constant proliferation and sustain processes such as migration and invasion. For this, they use membrane trafficking pathways to scavenge nutrients already available. Macropinocytosis allows the bulk internalization of extracellular ATP as well as albumin and other nutrients. In a similar manner, receptor-mediated endocytosis is responsible for the uptake of receptors and their ligands that will be degraded in the lysosomes providing new building blocks to be reused. Examples are integrins that bind to ECM components, and megalin which binds to albumin in the extracellular environment. The internalized albumin can either bind to neonatal Fc receptor inside the endosomes and be recycled back to the plasma membrane, or degraded in the lysosomes. To access the pool of nutrients already available in the cell, cancer cells can hijack autophagy. Engulfed damaged organelles and protein aggregates can thus be broken down and degraded in the lysosomes for reuse. The altered metabolism during cancer progression results in increased MT1-MMP recycling, thus promoting cell invasion.

FIGURE 2

Membrane trafficking events in EMT and cell invasion. Epithelial cells are organized in layers by establishing contacts with neighboring cells as well as the basement membrane. During cancer progression, the cells can lose these contacts leading to EMT and increased proliferation. Cancer cells can then acquire migratory ability, breaching through the basement membrane and invading into the ECM. (A) During EMT, E-cadherin is internalized and degraded. NUMB regulates the internalization and recycling of E-cadherin. When NUMB is lost, E-cadherin relocalizes to the apical side. Upon internalization, E-cadherin can be phosphorylated by src leading to ubiquitination by the E3 ligase Hakai. Ubiquitinated E-cadherin is delivered to lysosomes for degradation. This results in the loss of adherens junctions. N-cadherin is then transported to the surface promoting migration. (B) Trafficking of α5β1 integrin under low nutrient conditions. Inhibition of the mTORC1 activation and of its recruitment to lysosomes promotes Arf4-dependent endocytosis, α5β1 integrin recycling, and cell invasion.