Preclinical study links aging cells with lethal host metabolism in the tumour microenvironment
How aging normal cells influence on tumour growth and metastasis
- Date : 02 Jul 2012
- Topic : Personalised medicine
It has long been known that cancer is a disease of ageing, but a molecular link between the two has remained elusive. Now, researchers at the Kimmel Cancer Centre at Jefferson, USA have shown that senescence (ageing cells which lose their ability to divide) and autophagy in the surrounding normal cells of a tumour influence on cancer cell growth and metastasis.
Dr Michael Lisanti, Professor and Chair of Stem Cell Biology and Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the Kimmel Cancer Centre, and his team previously discovered that cancer cells induce an oxidative stress response (autophagy) in nearby cells of the tumour micro-environment to feed themselves and grow.
In this study, senescent cells appear to have many of the characteristics of these autophagic cancer-associated fibroblasts and to be part of the same physiological process. In other words, normal neighbouring cells that are becoming senescent or "old" are directly making food to "feed" the cancer. Ageing literally fuels cancer cell growth.
Since senescence is thought to reflect biological ageing, this research on autophagy-induced senescence may explain why cancer incidence dramatically increases exponentially with advanced age, by providing a "fertile soil" to support the anabolic growth of "needy" cancer cells.
The findings were reported in the June 15 issue of Cell Cycle.
New findings merge the two paradigms of ageing and cancer
In their work, the researchers provided genetic support for the importance of two-compartment tumour metabolism in driving tumour growth and metastasis via a very simple energy transfer mechanism. Senescence and autophagy metabolically support tumour growth and metastasis. More simply, ageing is the metabolic engine that drives cancer growth.
To test this link, the researchers developed a genetically tractable model system to directly study the compartment-specific role of autophagy in tumour growth and metastasis. First, they took human fibroblasts immortalized with telomerase and transfected them with autophagy genes.
Next, they validated that these fibroblasts show features of mitophagy, mitochondrial dysfunction and a shift toward aerobic glycolysis, with increases in lactate and ketone production, mimicking the behaviour of cancer-associated fibroblasts. They observed that autophagic-senescent fibroblasts promoted metastasis, when co-injected with human breast cancer cells, by more than 10-fold.
Thus, metastasis may be ultimately determined by ageing or senescent cells in the tumour micro-environment, rather than by the cancer cells themselves. This finding completely changes how we view cancer as a disease, by calling into question the long-standing notion that cancer is a cell-autonomous genetic disease. Rather, it appears that cancer is really a disease of host ageing, which fuels tumour growth and metastasis, thus, determining clinical outcome. Normal ageing host cells are actually the key to unlocking effective anti-cancer therapy, the researchers speculated.
In this study, the autophagic fibroblasts also showed features of senescence. What's more, the senescent cells shifted toward aerobic glycolysis, and were primarily confined to the tumour stromal compartment. Autophagy action is also clearly compartment specific, since the researchers showed that autophagy induction in human breast cancer cells resulted in diminished tumour growth. To stop tumour growth and metastasis, researchers will need to target autophagy and senescence in the tumour micro-environment.
Latest findings are paradigm shifting and will usher in a completely new era for anti-cancer drug development, according to the researchers. Such approaches for targeting the autophagy-senescence transition could have important implications for preventing tumour growth and metastasis, and effectively overcoming drug resistance in cancer cells.
The authors concluded that rapidly proliferating cancer cells are energetically dependent on the ageing host tumour stroma. As such, removing or targeting the ageing tumour stroma would then stop tumour growth and metastasis. Thus, the ageing stroma is a new attractive metabolic or therapeutic target for cancer prevention. An outcome of this research could also be the development new anti-ageing drugs to effectively combat, stop or reverse ageing, thereby preventing a host of human diseases, particularly cancer.
This work was supported by grants from the Breast Cancer Alliance the American Cancer Society, Young Investigator Award from the Margaret Q. Landenberger Research Foundation, grants from the NIH/NCI (R01-CA-080250; R01-CA-098779; R01-CA-120876; R01-AR-055660), and the Susan G. Komen Breast Cancer Foundation. Other grants include NIH/NCI (R01-CA-70896, R01-CA-75503, R01-CA-86072 and R01-CA-107382) and the Dr. Ralph and Marian C. Falk Medical Research Trust. The Kimmel Cancer Centre was supported by the NIH/ NCI Cancer Centre Core grant P30-CA-56036. This project is funded, in part, under a grant with the Pennsylvania Department of Health. This work was also supported, in part, by a Centre grant in Manchester from Breakthrough Breast Cancer in the UK and an Advanced ERC Grant from the European Research Council.
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