Study reveals how normal cells fuel tumour growth

Excised human breast tissue, showing a stellate area of cancer 2cm in diameter. The lesion could be felt clinically as a hard mobile lump, not attached to skin or chest wall. The histology was that of a moderately well differentiated duct carcinoma. (Image: John Hayman, via Wikimedia Commons)

• The study shows how normal cells in tumours can enhance the growth of the tumour's cancer cells after losing an important tumour suppressor gene called Pten.
  
• The findings suggest a new strategy for treating breast cancer by interrupting signals between normal cells and cancer cells in tumours.

Led by researchers at the Ohio State University Comprehensive Cancer Centre - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James), the study examines what happens when normal cells called fibroblasts in mouse mammary tumours lose an important tumour-suppressor gene called Pten (pronounced "P-ten").

The findings suggest new strategies for controlling tumour growth by developing drugs that disrupt the communication between tumour cells and the normal cells within the tumour. They also provide insight into the mechanisms that control the co-evolution of cancer cells and surrounding normal cells in tumours, and they demonstrate how the Pten gene normally suppresses cancer development, the researchers say.

A first

"Our study is the first to define a specific pathway in tumour fibroblasts that reprograms gene activity and the behaviour of multiple cell types in the tumour microenvironment, including tumour cells themselves," says co-principal investigator Dr. Michael Ostrowski, professor and chair of molecular and cellular biochemistry.

"Along with increasing basic knowledge about how tumours grow and spread, these findings have direct translational implications for the treatment of breast-cancer patients," says Ostrowski, who is a member of the OSUCCC - James Molecular Biology and Cancer Genetics program.

The researchers found that Pten regulates a molecule called microRNA-320 (miR-320), and that the loss of Pten leads to a dramatic drop in levels of that molecule in a tumour fibroblast. With little miR-320 around, levels of a protein called ETS2 (pronounced Ets-two) rise in the fibroblast.

Finally, the abundance of ETS2 activates a number of genes that cause the fibroblast to secrete more than 50 factors that stimulate the proliferation and invasiveness of nearby cancer cells. It also causes the reprogramming of other fibroblasts in the tumour and throughout the mammary gland.

"The cancer field has long focused solely on targeting tumour cells for therapy," says co-principal investigator Gustavo Leone, associate professor of molecular virology, immunology and medical genetics. "Our work suggests that modulation of a few key molecules such as miR-320 in non-cancer cells in the tumour microenvironment might be sufficient to impede the most malignant properties of tumour cells."

How the study began

Ostrowski, Leone and their colleagues began this study by examining human invasive breast tumours from 126 patients for microRNA changes after PTEN loss. Key technical findings include the following:

• Using mouse models, they found that miR-320 levels and ETS2 levels were inversely correlated in human breast-tumour tissue, suggesting that Pten and miR-320 work together to block ETS2 function and suppress tumour growth.
  
• miR-320 in mammary fibroblasts influences the behaviour of multiple cell types, making it a critical molecule for suppressing epithelial tumours.
  
• miR-320 functions as a regulatory switch in normal fibroblasts that operates to inhibit the secretion of more than 50 tumour-promoting factors (i.e., a tumour-promoting secretome). In doing so, it blocks the expression of genes in other cell types in the tumour microenvironment and suppresses tumour-cell growth and invasiveness.
  
• Overall, loss of Pten in tumour fibroblasts results in downregulation of miR-320 and release of the secretome factors. This causes the genetic reprogramming of neighbouring endothelial and epithelial cells of the mammary gland, inciting profound changes in these cells that are typical of malignant tumours.

"Remarkably, the molecular signature of the miR-320 secretome could distinguish normal breast tissue from tumour tissue, and it predicted the outcome in breast-cancer patients," says Leone, who is also a member of the OSUCCC - James Molecular Biology and Cancer Genetics program. "This underscores the potential clinical importance of the Pten-miR-320 regulatory pathway on human breast cancer."

Funding from the National Cancer Institute, National Institute of Child Health and Human Development, the Komen Breast Cancer Foundation and Evelyn Simmers Charitable Trust supported this research.

Other researchers in this study were Agnieszka Bronisz, Jakub Godlewski, Julie A. Wallace, Anand.S. Merchant, Michal O. Nowicki, Haritha Mathsyaraja, R. Srinivasan, Anthony J. Trimboli, Chelsea K. Martin, F. Li, L. Yu, Soledad A. Fernandez, T. Pécot, Thomas J. Rosol, M. G. Piper, Clay B. Marsh, Lisa D. Yee, G. Nuovo and E. Antonio Chiocca of Ohio State; S. Cory and M. Hallett and M. Park of McGill University; R. E. Jimenez14 of Mayo Clinic; and Sean. E Lawler of Leeds Institute of Molecular Medicine.

Source: Ohio State University