Tiny clues left behind by cancer may help scientists solve its mystery
Tiny, virus-sized particles released by cancer cells may be the next big thing in the world of cancer biology. Exosomes, derived from cells and blood serum of patients, have been shown to detect pancreatic cancer and, possibly, breast cancer, and are also linked to increased cancer progression and tumor growth.
They achieve this by manufacturing microRNA molecules with the help of proteins such as Dicer. New research led by MD Anderson’s Raghu Kalluri, M.D., Ph.D., chair of Cancer Biology, suggests Dicer may serve as a biomarker for breast cancer and could open up new avenues for diagnosis and treatment.
Exosomes are small vesicles consisting of DNA, RNA and proteins enclosed in a membrane made of two lipid layers. They perform specialized functions such as coagulation, intercellular signaling and cell “waste management.” They’re shed into bodily fluids, forming a source of disease-specific nucleic acids and proteins. Increasingly, exosomes are studied for their potential as both indicators of disease and as a prospective new treatment approach.
All exosomes contain a cellular stew of smaller components such as proteins, messenger RNA and microRNA. Kalluri’s team reported that breast cancer-associated exosomes have specific miRNAs associated with a multi-protein complex known as RNA-induced silencing complex (RISC).
In addition to RISC, the breast cancer exosomes house Dicer and two other proteins, AGO2 and TRBP, all of which combine to promote tumor growth.
“The role of microRNA associated with exosomes in cancer progression is largely unknown. Many studies have suggested the presence of microRNA in exosomes and speculated on their function,” Kalluri says. “We demonstrated that inhibiting Dicer’s action in cancer exosomes significantly impairs tumor growth, raising the possibility that microRNA in exosomes contribute to cancer progression.”
Kalluri’s study indicated that the interplay between Dicer and its “host” exosome may allow cancer cells to develop an “oncogenic field effect” by manipulating surrounding cells via exosomes. Think of a child blowing a dandelion’s spores into the wind, where they float over a freshly mown lawn, and one can envision how this molecular mixer easily spreads the disease to surrounding tissue.“These studies reflect the need to evaluate the functional contribution of microRNA machinery in exosomes, as well as their role in tumor progression and spread,” Kalluri says.
“We believe analysis of exosome DNA taken from blood samples can help determine the presence of a cancerous tumor somewhere in the body, as well as identify mutations without the need for a tumor sample.”
A simple blood test
Thanks to exosomes, which contain the entire genetic blueprint of cancer cells, Kalluri and his team believe it’s possible that a simple blood test could be developed to determine if gene mutations associated with pancreatic cancer exist without locating and testing tumor tissue. By decoding this genomic data and looking for deletions and mutations associated with cancer, the discovery could result in a test for detecting cancer.
“There’s no single blood test that can screen for all cancer-related DNA defects,” Kalluri says. “In many cases, protocols require a tumor sample to determine whether gene mutations and deletions exist and, therefore, determine if the tumor is cancerous or benign. To procure tumor tissue, one needs to know that a tumor exists and, if so, is it accessible for sample collection or removal? Finally, there are always risks and significant costs associated with surgical procedures to acquire tumor tissue.”
Scientists have long known that exosomes contain portions of a person’s DNA, but it was Kalluri’s team that discovered a patient’s entire double-stranded genomic DNA spanning all chromosomes — including those mutated chromosomes that cause various cancers — can be found in exosomes. They also found that DNA derived from exosomes carries the same cancer-related genetic mutations compared to the cancer cells taken from tumors.
“Because different forms of cancer are associated with different chromosomal mutations, we believe analysis of exosome DNA taken from blood samples can help determine the presence of a cancerous tumor somewhere in the body. It can also identify mutations without the need for a tumor sample,” Kalluri adds. “We believe this `fingerprint’ will help lead us to the likely site of the tumor in the body.”
Kalluri acknowledges that further study is necessary to develop a blood test, but having such a tool would increase physicians’ abilities to detect cancer earlier and, therefore, increase chances for effective treatment.
