Soil Amendments That Slow Cancer Growth

Cancer research over the last quarter century has focused almost exclusively on identifying the molecular features of cancer cells based on the idea that genomic changes are in and of themselves the drivers of cancer. Thus, in their original review, Hanahan and Weinberg attributed the six hallmarks of cancer to genetic alterations within the cancer cell. Similarly, experimental rodent models of cancer focused predominantly on "targets," that is, the genome of the cell that underwent neoplastic transformation, which afforded a great deal of insight into pathways that are deregulated by genetic aberrations and paved the way for targeted therapeutics.

This focus on the cancer cell genome overshadowed the essential contribution of the tumor microenvironment. The genetic changes occurring in cancer cells were known to affect the microenvironment, but their acquisition was considered to be stochastic. A notable exception was Folkman's early recognition that vascularity could be the Achilles heel of tumors. Even so, antiangiogenic targets are often conceived of as a means of depriving the autonomous cancer cell of nutrients rather than modifying a necessary cellular partner in neoplastic growth.

As reflected in the updated Hanahan and Weinberg review, the past decade has witnessed increasing acknowledgment that the tumor microenvironment provides the context for carcinogenesis. We now recognize that the key to malignant cells successfully seeding cancer is proper amendment of the soil during neoplastic progression, and that for cancer to evolve from early dysplastic lesions into invasive cancer, malignant cells must continue to modify the tissue in an organ-specific manner to facilitate survival. Thus, the acquisition of mutations, such as activation of oncogenic signaling pathways, by early cancer cells not only promotes cancer cell growth but may also act on the surrounding tissue to recruit and activate stromal cells and reprogram the microenvironment. Therapeutically targeting the tumor microenvironment is now attractive because, compared with the variable routes taken by cells to become cancers, the response of tissues to cancer is relatively consistent. This idea raises the possibility that controlling and eliminating cancer may be more readily achieved indirectly via the tissue microenvironment.

Cancer-associated fibroblasts (CAF) are biologically distinct from resident tissue fibroblasts and are functionally polar opposites. Normal stroma can actively suppress tumor growth, but a shift of programming converts quiescent fibroblasts into CAFs, whose action promotes tumorigenesis. Intriguingly, senescent fibroblasts, which accumulate with age, also display protumorigenic activity. Comparison of the secretory phenotype of CAFs and senescent fibroblasts revealed an overlap in expression of secreted factors referred to as senescence-associated secretory phenotype (SASP) factors. These observations raise the question of how this common secretory phenotype is regulated and whether it provides a therapeutic opportunity.

The new study by Alspach and colleagues in this issue describes a posttranscriptional mechanism mediated by p38MAPK activity on AUF1 to stabilize SASP mRNA species common to both CAFs and senescent fibroblasts. The studies are carefully laid to make a compelling argument in support of their major conclusion that p38MAPK inhibitors, now in clinical trials for other disease states, may be useful in cancer therapy by targeting the stromal cell contribution to cancer growth.

Numerologist Warda is hooked on OG-L002 fishing, collecting. And lastly her encouragement comes from socializing along with her companions.