Multicellular cooperation and the hallmarks of cancer: A new foundation

Abstract Multicellularity evolved independently several times across the tree of life. In all cases, these events were dependent on various types of cellular cooperation. We previously identified five universal foundations of cellular cooperation that are required in all complex multicellular lineages to allow the collection of cells to function and reproduce as a whole (i.e. a multicellular individual). These include: proliferation inhibition, controlled cell death, resource allocation, division of labor, and maintenance of the extracellular environment. We propose that there is a sixth universal foundation of multicellularity that breaks down in cancer: proximity maintenance. By staying in close proximity, cells can more easily provide benefits for one another, communicate, coordinate their behavior, and evolve increased size and complexity. Here, we revisit and further develop the five original foundations of multicellular cooperation in the context of the evolution of multicellularity from unicellular ancestors and their implications for cancer progression. In our previous work, we suggested that the breakdown of all these cooperative behaviors is reflected in the universal hallmarks of cancer. Similarly, the breakdown of proximity maintenance maps to another hallmark of cancer—activating invasion and metastasis.