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Intratumor heterogeneity (ITH), referring to coexistence of different cellsubpopulations in a single tumor, has been a major puzzle in cancer researchfor almost half a century. The lack of understanding of the underlyingmechanism of ITH hinders progress in developing effective therapies forcancers. Based on the findings in a recent quantitative experiment onpancreatic cancer, we developed a general evolutionary model for one type ofcancer, accounting for interactions between different cell populations throughparacrine or juxtacrine factors. We show that the emergence of a stableheterogeneous state in a tumor requires an unequal allocation of paracrinegrowth factors ("public goods") between cells that produce them and those thatmerely consume them. Our model provides a quantitative explanation of recent{\it in vitro} experimental studies in pancreatic cancer in which insulingrowth factor (IGF-II) plays the role of public goods. The calculated phasediagrams as a function of exogenous resources and fraction of growth factorproducing cells show ITH persists only in a narrow range of concentration ofexogenous IGF-II. Remarkably, maintenance of ITH requires cooperation amongtumor cell subpopulations in harsh conditions, specified by lack of exogenousIGF-II, whereas surplus exogenous IGF-II elicits competition. Our theory alsoquantitatively accounts for measured {\it in vivo} tumor growth in glioblastomamultiforme (GBM). The predictions for GBM tumor growth as a function of thefraction of tumor cells are amenable to experimental tests. The mechanism forITH also provides hints for devising efficacious therapies.

Share, but unequally: A plausible mechanism for emergence and maintenance of intratumor heterogeneity