Hallmarks of Cancer: New Dimensions

The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underl y-ing principles. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refi nements. Herein, the prospect is raised that phenotypic plasticity and dis-rupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogram-ming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities. Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. Significance: Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Ever more powerful experimental and computa-tional tools and technologies are providing an avalanche of big data about the myriad manifestations of the diseases that cancer encompasses. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimen-sions presented in this perspective may add value to that endeavor, to more fully understand mecha-nisms of cancer development and malignant progression, and apply that knowledge to cancer medicine.

Automated summary

The concept of the hallmarks of cancer is a tool for simplifying the complexity of cancer phenotypes and genotypes into basic principles. This article proposes phenotypic plasticity and disrupted differentiation as distinct hallmark capabilities, and discusses nonmutational epigenetic reprogramming and polymorphic microbiomes as enabling characteristics. Additionally, the importance of senescent cells in the tumor microenvironment is highlighted. The integrative concept of the hallmarks of cancer helps in understanding the mechanisms of cancer development and applying that knowledge to cancer medicine.