The Tumor Micro-environment (Short)

In current cancer research, the tumor microenvironment is coming more and more into the focus as it is able to either promote or inhibit carcinogenesis and metastasis by providing cancer cells with growth factors and supply of oxygen and nutrients. The stroma of tumors is enriched for chemokines, which attract and activate various other cell types, including cancer-associated fibroblasts (CAF). These cells closely interact with cancer cells, secrete cytokines, remodel the extracellular matrix and thereby promote malignancy (1). Importantly, age is one of the main risk factors for many types of cancer and is accompanied by an accumulation of senescent cells in various tissues of the body. As senescent cells actively shape their tissue microenvironment in a similar fashion as CAF toward a pro-tumorigenic state (2), cellular senescence (together with the well-known mutation accumulation over a lifetime) is probably one of the main contributors to age-associated cancer development.

Cellular senescence, a state of irreversible growth arrest, was discovered by Leonard Hayflick more than 50 years ago (3). A whole new field of investigation was opened up by this seminal discovery that was over the last 50 years closely intertwined with research in organismic aging, which was of obvious primary interest, but also with several other closely related fields, like oxidative stress research, origin of reactive oxygen species (ROS), role of mitochondria in aging, role of telomeres and telomerase in aging, and the genetics of stress response and stress defense. From early on in this field, the hypothesis was entertained that (i) the phenomenon observed in mammalian cell culture indeed occurs in vivo and drives normal organismic aging and (ii) induction of senescence was positively selected for in evolution for several reasons, among them to protect cells and organisms from cancer. Both of these ideas were highly speculative, but over the last 20 years were shown to be correct in part (2, 4–8). On the other hand, reports that establish a beneficial and important role of cellular senescence in embryogenesis (9, 10) and wound healing (11) imply that senescence might have evolved for other reasons as well.

The Central Argument

The basic arguments about the role of senescence in cancer protection are as follows: senescent cells have lost the ability to undergo cell division permanently, although they may be metabolically fully active. This would certainly protect individuals carrying a primary cancer from further cancerous growth. However, this has to be seen in a different way nowadays as compared to the time when this “anticancer hypothesis” was first published (8), as knowledge of the genetics of cancer and senescence increased rapidly over the last few years. By this, we mean on the one hand the sequence of mutational events that takes place in growing tumors (12, 13), and on the other hand the knowledge of biochemical senescence markers in senescent cells in vivo (6, 14–17). Most importantly, senescent cells may be prone to genetic and epigenetic instability (18, 19), which is also a hallmark of cancer cells (12). In addition, the senescence-associated secretory phenotype (SASP) directly causes transformation of neighboring cells and destruction of the extracellular matrix, other hallmarks of cancer growth, which help to spread malignant cells in the body (2, 20, 21). Thus, cellular senescence can be viewed as a typical example for antagonistic pleiotropy: at young age, senescence might protect cells from transformation into primary tumors; however, at old age senescent cells generate a pro-tumorigenic microenvironment.

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References

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3. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res (1961) 25:585–621.10.1016/0014-4827(61)90192-6 [PubMed] [CrossRef]

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17. Evangelou K, Lougiakis N, Rizou SV, Kotsinas A, Kletsas D, Muñoz-Espín D, et al. Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging Cell (2017) 16:192–7.10.1111/acel.12545 [PMC free article] [PubMed] [CrossRef]

18. De Cecco M, Criscione SW, Peckham EJ, Hillenmeyer S, Hamm EA, Manivannan J, et al. Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell (2013) 12:247–56.10.1111/acel.12047 [PMC free article] [PubMed] [CrossRef]

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