Fig. 5
Breast tumor as a dynamic social system manifesting altruistic cooperation. A In altruistic cooperation, a small subpopulation of altruistic cells (blue) confers communal protection against taxane exposure by secreting trophic factors (IGFBP2 and CCL28) that activate PI3K/AKT signaling and thus leading to heightened chemotolerance in neighboring cells (yellow). During post-treatment expansion phase, the altruistic subpopulation, saddled with a fitness disadvantage due to miR-125b-mediated cell cycle impediment, risks becoming extinct due to competition from the faster growing neighboring non-altruists. B Conferment of survival benefits to others (an oncogenic event) and incurring of fitness cost to self (a tumor suppressive event), both of which are defining attributes of altruism, are found to be commonly mediated by heightened miR-125b expression, via differential NF-κB signaling, in the altruistic cancer cells. C The altruistic subpopulation persists, due to phenotypic conversion from the neighboring non-altruists via a KLF2/PCAF-mediated epigenetic mechanism acting on the promoter of the hsa-miR-125b-1 gene. D The tumor cell population actively self-organizes via a lateral inhibition mechanism mediated by IGFBP2/CCL28-induced GAB1-PI3K-AKT-miR-125b signaling circuit. This limits the altruistic subpopulation to a minority presence and a sparse spatial arrangement. A closer look at the lateral inhibition model (below) shows inhibition of GAB1 by high miR-125b expression in the altruist, which prevents self-activation of PI3K/AKT by the altruists-secreted IGFBP2 and CCL28, thus averting self-benefiting and instability of the altruistic phenotype. E The lateral inhibition mechanism, coupled with epigenetic regenerability of the altruists, permits stable co-existence of functionally distinct subpopulations: an altruistic miR-125bHigh minority confers costly communal protection during chemotherapeutic crisis while the miR-125bLow majority undergoes aggressive proliferation post-crisis to re-colonize the tumor. Cooperation between these different phenotypes suggests the existence of division of labor, a hallmark of complex biological societies, within the breast tumor. F One possible explanation of the origin of altruistic tumor society is evolution from a homogeneous population of generalist cancer cells. The composition of the resulting altruistic society of cancer cells can theoretically be perturbed with varying ecological consequences. Without epigenetic regeneration of altruists, non-altruists or “cheats” would dominate and deplete existing resources, leading to a situation called the “tragedy of the commons” [53]. Conversely, without lateral inhibition, altruists would dominate the population, hence inflicting a fitness burden on the tumor. Breast tumor may thus constitute a potential model to study how tumor-specific ecological factors can affect evolution and manifestation of altruistic cooperation. G Examples of altruistic social systems and how the social dynamics is regulated. Above: In honeybee (Apis Mellifera), the queen bee secretes primer pheromone such as CHCs and other glandular compounds that suppress worker ovarian development, thus maintaining the workers as reproductive altruists [64]. In Dictyostelium amoeba, the pre-spores secrete differentiation-inducing factor-1 (DIF-1) to prevent the altruistic pre-stalk cells from developing into spores, thus maintaining a 80:20 spore-to-stalk cell ratio in the fruiting body that is formed eventually [65]. Such secretion-mediated regulation of cell fate is similarly observed in the altruistic breast cancer cells. Below: Epigenetic regulation is known to underlie behavioral plasticity in Apis Mellifera [57], and we likewise observed how epigenetic mechanism regulates social fate plasticity in breast cancer cells