Category Archives: Transhuman News

Rachel Philipson

Ph.D. student and study co-author Sachi Horibata and Scott Coonrod, associate professor at the Baker Institute for Animal Health, work on research that linked an enzyme to cancer development.

New research on an enzyme linked to cancer development shows that 37 percent of mice that produce excessive quantities of the enzyme developed skin tumors within four to 12 months of birth, and many of these growths progressed to highly invasive squamous cell carcinoma, a common form of skin cancer.

This finding, published online Sept. 11 in the journal Cancer Research, provides the first genetic link between the activity of the enzyme, called PAD2, and cancer progression, and provides important supporting evidence for further studies aimed at using PAD2 inhibitors to block carcinoma progression in humans.

Lead author Scott Coonrod, the Judy Wilpon Associate Professor of Cancer Biology at the Baker Institute for Animal Health in Cornells College of Veterinary Medicine, has studied links between PAD2 and other PAD (peptidylarginine deiminase) enzymes and cancer for some time. Those prior studies suggested that PAD2 plays an important role in regulating genes during cancer progression; however, a direct link between PADs and tumor progression had not yet been proven. Other work from the lab suggested that PAD2 is found at high concentrations in several tumor types, but it was not known whether these elevated levels of the enzyme were causing cancer or merely a consequence of tumor progression.

To directly test for links between PAD2 and cancer, the researchers engineered mice to overexpress PAD2 and then looked to see whether these mice developed cancer.

Coonrod thinks that the reason PAD2 overproduction in the skin may cause cancer is likely due to its ability to promote inflammation.

Inflammation has long been known to play an important role in the development of many types of cancer, he says. Recent studies provide strong evidence that inflammation represents one of the 10 hallmarks of cancer.Its becoming clear that the activity of PAD enzymes seems to be low in most normal tissues, but becomes elevated in a whole range of inflammatory diseases like rheumatoid arthritis, colitis and lupus. PAD activity is very high in the affected tissues and seems to be driving a lot of the inflammatory conditions that cause these diseases.

To test whether PAD2 might be promoting inflammation, Coonrod and his colleagues looked for classical markers of inflammation in the growths and found that a number of these markers were significantly elevated in the mouse tumors. To further test their hypothesis, they overexpressed PAD2 in human cell lines to better understand how the enzyme might behave in human tissue. They found that, similar to the mouse studies, PAD2 overproduction made these human cells more invasive and also enhanced inflammatory marker expression.

Together, these studies suggest that increased PAD activity in human skin, and potentially other tissues, promotes an inflammatory environment that is favorable for cancer development, says Coonrod. His longtime collaborator, Paul Thompson at the University of Massachusetts Memorial Medical Center, has developed a range of new PAD inhibitors, and the team is now testing whether these compounds might suppress carcinoma progression in mouse models of both skin and mammary glands.

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Gene linked to development of skin cancer in mice

PUBLIC RELEASE DATE:

22-Sep-2014

Contact: Katie Marquedant kmarquedant@partners.org 617-726-0337 Massachusetts General Hospital @MassGeneralNews

Analysis of circulating tumor cells (CTCs) in a mouse model of pancreatic cancer identified distinct patterns of gene expression in several groups of CTCs, including significant differences from the primary tumor that may contribute to the ability to generate metastases. In their study reported in the Sept. 25 issue of Cell Reports, investigators from the Massachusetts General Hospital (MGH) Cancer Center identified several different classes of pancreatic CTCs and found unexpected factors that may prove to be targets for improved treatment of the deadly tumor.

"Our ability to combine a novel microfluidic CTC isolation device, developed here at MGH, with single-cell RNA sequencing has given us new biological insights into these cells and revealed novel avenues to try and block the spread of cancer," says lead author David T. Ting, MD, MGH Cancer Center.

Pancreatic cancer is among the most deadly of tumors because it spreads rapidly via CTCs carried in the bloodstream. The earliest technologies for isolating CTCs from blood samples relied on interactions with known tumor-specific marker proteins, potentially missing cells that did not express those particular markers. The device used in the current study, called the CTC-iChip, enables the isolation of all CTCs in a blood sample, regardless of the proteins they express on their surface, by removing all other components. Since the CTCs collected are in solution, unlike with previous CTC capture devices, they are suitable for advanced RNA sequencing techniques to reveal the gene expression patterns of each individual cell.

Using a well-known mouse model of pancreatic cancer, the researchers first isolated 168 single CTCs from the bloodstreams of five individual mice. Analysis of the RNA transcripts of each CTC revealed several different subsets of CTCs, based on gene expression patterns that were different from each other and from the primary tumor. The largest subset, which the authors call 'classic CTCs,' was found to have elevated expression of a stem cell gene called Aldh1 a2, along with genes characteristic of two basic cell types epithelial and mesenchymal transition between which has been associated with tumor metastasis. Another gene expressed by almost all classic CTCs, Igfbp5, is only expressed in primary tumor at locations where epithelial cancer cells interface with the supporting stromal cells that provide a nurturing microenvironment, an observation that suggests that those regions may be the source of CTCs.

The research team was most surprised to observe that extracellular matrix (ECM) genes in general usually expressed primarily in stromal cells were highly expressed in all classic CTCs. Previous studies have suggested that the establishment of metastases depends on the appropriate cellular microenvironment 'soil' in which CTCs can plant themselves as 'seeds' and that the expression of ECM genes is an important aspect of that environment. Expression of ECM genes by CTCs themselves suggests that the blood-borne cells may provide or help prepare their own 'soil.'

Analysis of CTCs from blood samples of human patients with pancreatic, breast or prostate cancer also found elevated expression of several ECM genes. One particular gene, SPARC, was highly expressed in all pancreatic CTCs as well as in 31 percent of breast CTCs. Further experiments revealed that suppressing SPARC expression in human pancreatic cancer cells reduced their ability to migrate and invade tissue, and significantly fewer metastases were generated when SPARC-suppressed pancreatic tumors were implanted into a mouse model, supporting the protein's role in a tumor's metastatic potential.

"Given our limited therapeutic options for pancreatic cancer, understanding the role of the ECM in this tumor seems to be of great importance," says Ting, who is an assistant professor of Medicine at Harvard Medical School. "Much effort has been focused on targeting the microenvironment to improve the efficacy of chemotherapy, and data indicating that environmental stromal cells can enhance a tumor's metastatic ability indicate that ECM proteins are important whether they are produced in stroma or within the tumor cells themselves. Now we need to investigate whether therapeutically targeting ECM can destroy both the tumor microenvironment and CTCs before they have a chance to metastasize."

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Massachusetts General study reveals gene expression patterns in pancreatic CTCs