Factors in the Tumor Microenvironment Promote Cancer Growth and Metastasis

Cancer researchers have found that procancerous HSF1 (Heat shock factor 1) drives a transcriptional program in cancer-associated fibroblasts (CAFs) that complements, yet is completely different from, the program it drives in adjacent cancer cells.

Stromal cells within the tumor microenvironment are essential for tumor progression and metastasis, but little is known about the factors that drive the transcriptional reprogramming of stromal cells within tumors. Investigators at the Whitehead Institute for Biomedical Research (Cambridge, MA, USA) recently reported that the transcriptional regulator heat shock factor 1 (HSF1) was frequently activated in cancer-associated fibroblasts (CAFs), where it was a potent enabler of malignancy. HSF1 activity was found in a variety of human tumors, including breast, lung, skin, esophageal, colon, and prostate cancers.

HSF1 is the major regulator of heat shock protein transcription in eukaryotes. In the absence of cellular stress, HSF1 is inhibited by association with the heat shock proteins Hsp40/Hsp70 and Hsp90 and is therefore not active. Cellular stresses, such as increased temperature, can cause misfolding of proteins in the cell. Heat shock proteins bind to the misfolded proteins and dissociate from HSF1. This allows HSF1 to form trimers and translocate to the cell nucleus where it is hyperphosphorylated, binds to DNA containing heat shock elements, and activates transcription.

The investigators reported in the July 31, 2014, issue of the journal Cell that analysis of tumor samples from breast cancer and non-small-cell lung cancer patients revealed that HSF1 activation in the stroma was associated with poor patient outcomes, including reduced disease-free survival and overall survival. Thus, stromal HSF1 is considered to be a possible biomarker for cancer diagnosis and prognosis as well as a potential drug target.

“This is actually a beautiful example of evolution,” said Dr. Ruth Scherz-Shouval, a postdoctoral researcher at the Whitehead Institute for Biomedical Research. “It is recognizing that the tumor is like an organism that adheres to evolutionary principles. HSF1 has been highly conserved over time, supporting the survival of organisms ranging from yeast to human, so it makes sense that it is coopted here. Both cancer cells and the microenvironment are sensing changes in the tumor and responding, signaling to one another to help the “organism,” albeit to the detriment of the host. These are different programs, but they are both controlled by HSF1 and serve the same purpose.”

“It is important to find HSF1 operating this way in the stroma,” said Dr. Scherz-Shouval. “The tumor microenvironment tends to be more genetically stable and less prone to mutation, suggesting that even if cancer cells could mutate to evade therapeutic disruption of HSF1, supportive cells in the stroma could still be susceptible.”

Related Links:
Whitehead Institute for Biomedical Research