Sunday, 10 June 2012

How Cancers Spread At Cellular Level - Scientists Find Clues

Weill Cornell Medical researchers from the Memorial Sloan-Kettering Cancer Center and their collaborators may have discovered an explanation that could provide a new insight into the 'soil and seed' theory. In an article recently published online in Nature Medicine, they have described a new mechanism to control the metastasis of cancer that could potentially be used as a novel diagnostic tool and treatment option.

Exosome vesicles are a specific subtype of membrane vesicles that circulate in the blood and contain numerous proteins, lipids, and even nucleic acids. In their study, the researchers managed to demonstrate a mechanism by which melanoma cancer cells release small exosome vesicles that travels to various locations, such as the brain, bone, liver and lungs, where the cellular material inside the vesicles fuses with these organs, establishing the perfect environment to spread tumor cells.

The researchers point out that these harmful cancer exosomes can cause various effects; For instance, they are able to trigger inflammation, further the process of leaky blood vessels and 'program' bone marrow progenitor cells to get involved in a soon-occurring metastatic cascade. Exosomes could potentially be advantageous in the diagnoses, prognosis and treatment of cancer, given that they are readily accessible and measurable as they circulate in the bloodstream.

Dr. David C. Lyden, the Stavros S. Niarchos Associate Professor in Pediatric Cardiology and associate professor of Pediatrics and Cell and Developmental Biology at Weill Cornell Medical College, who is also a pediatric neuro-oncologist at Memorial Sloan-Kettering Cancer Center explained: "The exosome profile could be useful in a number of ways - to help detect cancer early, to predict the aggressiveness of a patient's tumor and response to chemotherapy or other treatments, and to understand the risk of cancer recurrence or spread before traditional methods would be able to."

Dr. Jacqueline F. Bromberg, who studies breast cancer, and who is an associate attending physician at Memorial Sloan-Kettering Cancer Center and associate professor of Medicine at Weill Cornell, adds: "We believe each tumor type will have its own exosomal protein profile that will represent each tumor subtype. The exosomal proteins will be useful for prognosis in predicting which patients, including those who develop disease decades after their original diagnosis, will likely be at risk for future metastatic disease."

According to leading author, Dr. Hector Peinado, an instructor of molecular biology at Weill Cornell Medical College's Department of Pediatrics, the findings indicate that if a cancer therapy is to be effective, it has to be multi-layered, saying: "If, in the future, we were able to find a way to control the 'education' of bone marrow cells, as well as the release and content of tumor exosomes in cancer patients, we would be able to curtail and reduce the spread of cancer, and improve the patient's quality of life and survival."

Co-senior author, Dr. Lyden and his team were the first to discover that cells derived from bone marrow (BMDCs) were crucial in order to form primed sites in distant organs, called 'pre-metastatic niches' that provide a perfect base for cells that are spread from a primary tumor. For years they have investigated decoding the biochemical processes that produce these niches, trying to understand the signals that induce the BMDCs to carry out their functions in the niche. At first they investigated exosomes, which were originally believed to consist of mere cell debris used to dump used proteins, but were later found to contain RNA as well as nucleic acids that is found in cancer cells.

They decided to investigate whether exosomes released from a melanoma played a particular role in cancer, and according to Dr. Lyden they discovered:

"Upon their release from the primary tumor, exosomes derived from melanoma cells fuse with cells in distant metastatic organs and lymph nodes, mediating vascular leakiness and inflammation, thereby promoting the formation of pre-metastatic niches that enhance future metastatic growth."

Dr. Peinado explains that the exosomes transfer numerous exosomal proteins to BMDCs, where they are able to reprogram the cells to get involved in the metastatic cascade, saying "We found an oncogenic protein, called MET, that is produced by highly metastatic tumors and packaged into pro-metastatic exosomes. The tumor exosomes circulate, fuse and transfer their information, including the MET oncoprotein, to many cells, such as bone marrow cells, which in turn promote a pro-metastatic phenotype."

In addition, they also discovered that the reprogramming of the BMDCs by exosomes has a long-term effect. This could potentially explain why tumors can lie dormant for years before they suddenly develop into metastatic disease. According to Dr. Bromberg, these findings are vital given that "educated bone marrow is the key in disease recurrence and may even foster a future secondary cancer."

The researchers discovered after examining human blood samples, that patients with stage IV melanoma with widespread metastases had a specific signature of exosomal proteins (including MET), which was not discovered in the blood of patients with non-metastatic melanoma.

According to the researchers, this protein signature could serve as a potential marker to predict which patients with stage III disease and local lymph node metastasis would subsequently be at risk for developing distant metastatic disease.

Dr. Lyden states: "Treatment modalities could be initiated earlier in these high-risk patients to prevent disease progression. Our results demonstrated that MET oncoprotein expression, which can be easily analyzed in a simple blood test, could be used as a new marker of metastatic disease in melanoma patients."

After investigating further, the team found that they could reduce exosomal-induced metastasis either by targeting Rab27a, the protein responsible for production of exosomes or by proactively using exosomes derived from melanoma cells that rarely metastasize in order to reprogram the BMDCs.

Dr. Lyden concludes:

"We have found that less or non-metastatic exosomal proteins may educate bone marrow cells to avoid partaking in the metastatic process. We are working on determining which particular exosomal proteins may be responsible for preventing metastatic participation. This concept may one day be applied to the clinic, where non-metastatic exosome proteins may help prevent the acceleration of tumor growth and metastatic disease, allowing patients with cancer to live longer lives."

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