In 2000, the seminal paper “The Hallmarks of Cancer” was published by Douglas Hanahan, PhD, and Robert A. Weinberg, PhD, in the journal Cell. The authors provide evidence to support a multistep progression of alterations that drive normal cells into malignant cells that can survive, proliferate and spread. Hanahan and Weinberg proposed six acquired capabilities of cancer [Acquired Capabilities]. Briefly, these capabilities include evading apoptosis; self-sufficiency in growth signals; insensitivity to anti-growth signals; tissue invasion and metastasis; limitless replicative potential; and sustained angiogenesis. Importantly, in this manuscript published nearly two decades ago, Hanahan and Weinberg forecast that the immune system could serve as “active collaborators” in the initiation and progression of cancer [Tumors as Complex Tissues].
Acquired Capabilities of Cancer
Source: Hanahan D, Weinberg RA. Cell. 2000;doi:10.1016/S0092-8674(00)81683-9.
Tumors as Complex Tissues
Source: Hanahan D, Weinberg RA. Cell. 2000;doi:10.1016/S0092-8674(00)81683-9.
The original “The Hallmarks of Cancer” paper was updated in 2011. The revised manuscript “The Hallmarks of Cancer: The Next Generation” was expanded to include two emerging hallmarks: deregulating cellular energetics and evasion of immune destruction. Additionally, Hanahan and Weinberg describe enabling characteristics: genome instability and tumor-promoting inflammation [Emerging Hallmarks and Enabling Characteristics].
Emerging Hallmarks and Enabling Characteristics
Source: Hanahan D, Weinberg RA. Cell. 2011;doi:10.1016/j.cell.2011.02.013.
Typically, we think of our immune system as an ally; however, our immune system actually plays a role in promoting tumor growth. Tumor-promoting inflammation refers to early innate immune mechanisms driven by the tumor itself to promote tumor growth. One of the best described mechanisms is the role played by macrophages during early carcinogenesis in promoting angiogenesis and tissue remodeling without triggering anti-tumor immunity. This mechanism is actively promoted by the tumor through production of cytokines/chemokine and modulators of metabolic pathways (e.g., IDO and Arg1) rather than neoantigen recognition and lymphocyte involvement. In most solid tumors, various cells are found in the evolving tumor microenvironment and can contribute to inflammation [The Cells of the Tumor Microenvironment].
The Cells of the Tumor Microenvironment
Source: Hanahan D, Weinberg RA. Cell. 2011;doi:10.1016/j.cell.2011.02.013.
Hanahan and Weinberg go on to briefly describe the theory of immune surveillance and describe how some solid tumors seem to avoid detection by the immune system. Mouse models have been used to demonstrate that carcinogen-induced tumors were more likely to develop or grow more rapidly when mice were immunodeficient, especially when cytotoxic T lymphocytes (CTLs), helper T cells or natural killer (NK) cells were deficient. Several studies of human colon and ovarian tumors demonstrated that tumors with high infiltration of CTLs and NK cells had better prognosis. Evidence supporting the immune evasion hallmark continues to be published in journals across tumor sites, including, but not limited to, breast, lung, melanoma and lymphoma.
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