Cellular Function and Aging Tumor

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A very unique finding was the comparison of cancer cells from prostate and senescent cancer cells from prostate cultures. These tumor cell lines showed a near overlap between the proteins secreted before and after senescence indicating that senescent cell SASP's are similar to the proteins secreted by tumor cells. A further extension of this study looked at cells obtained from tumor biopsies before and after chemotherapy which showed significant upregulation of SASP production after chemotherapy. The authors conclude that chemotherapy results in some senescence within cells as the tumors after chemotherapy contain higher levels of RNA associated with the SASP's found in the cell studies.

Of critical importance to chemotherapy and oncology treatment, the authors linked the production of SASP to a condition where malignant tumor cells can break free from the rumor location and travel through the lymphatic system to other organs. The results showed that senescent cells in metastatic breast cancer tumors secrete proteins that lead adjacent cells to upregulate proteins allowing movement beyond the tumor capsule or basement membrane. The data links the idea that a SASP can directly affect cells near a senescent cell and have deleterious effects such as migration of malignant cells from a deadly cancer.

The authors then deliberately expressed a gene within cells specifically designed to promote cancer. This gene is called an oncogene and is used to induce a malignant behavior in cells and the resulting cells can be studied for SASP production. In this cell line, the oncogene called RAS was used to form a malignant cell that produced SASP's. The SASP's produced by cells infected with RAS oncogene then senesced through normal pathways of tumor inhibition, however, the SASP's generated by these induced tumor cells affected nearby cells and induced tumor-forming cells nearby in non-infected cells. In effect, the senescent tumor cells were capable of forming new tumor cells through secreted proteins. When the tumor suppressive protein, p53 was studied for cells before and after oncogenic inducement it was found that p53 not only could induce senescence but also restrain SASP production. The critical nature of this research showed that although p53 can induce senescence, the tumor suppressor protein also modifies the SASP production protecting surrounding cells from harm by the secreted proteins.

Aging is a combination of multiple factors, however, many of the effects of aging are linked to the finding of senescent cells in tissue where local inflammatory factors lead to tissue damage and misbehavior of nearby cells. The elimination of p53 appears to have an effect on the number of senescent cells formed, however, this missing tumor suppression protein then results in highly abundant SASP's further complicating the effect of having senescent cells in tissue in the first place. The results demonstrate that although p53 tumor suppression protein may appear to be a method of halting both cellular senescence and reducing aging, cellular senescence in effect may be present for many reasons outside of tumor suppression and the resulting secretory proteins are more harmful than the suppressed cells with p53 present. The nature of p53 remains a dual sword, however, the protein appears more beneficial than first assumed in that suppression involves more than simple inducement of senescence; the protein appears to also prevent the formation of SASP's and slow the effects of aging.

The potential for this work to be used in therapy development for limiting aging lies in the promise of limiting the harm or eliminating the life of senescent cells. If apoptosis (programmed cell death) can be performed on cells that have exceeded their useful life rather than leaving them present then the associated SASP production can be limited as well. Returning to the immortal Hydra, it may be more critical to insure that cell turnover continues unabated and damaged cells are removed quickly and efficiently so that there is no harm to tissue from the secretions of wounded senescent cells.

References

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