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Researchers Use Proteomic Techniques to Diagnose Prostate Cancer in Ancient King

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A team of German and Russian investigators have used proteomic technologies to determine that prostate cancer found in a Scythian king who ruled 2,700 years ago in southern Siberia — the oldest known diagnosis of the disease — is morphologically identical to recent cases.
 
In a study published in the Dec. 17 edition of the International Journal of Cancer, the researchers say the methods they used are new for the study of extracellular matrix proteins extracted from recent and ancient macerated bone samples. Their technique, they add, “is a precondition for the detection of tumor markers [such as prostate-specific antigens] in macerated bones.”
 
They say the goal of their work was to gather data on ancient disease “from the dawn of civilization … because the knowledge of the nature, etiology and epidemiology of ancient disease might provide insights into … future health problems.”
 
“There is no reliable information at the microscopic or proteomic levels on the nature, occurrence, and mode of metastases of ancient tumors, which would be useful for the understanding of the history and evolution of tumorous diseases,” the researchers report in their study. “However, such investigations are interesting because certain types of cancer that these days are estimated to be characteristic of our own times and frequently described as being due to our Western civilization are also found in antiquity.”
 
The research is built upon research done by Tyede Schmidt-Schultz and Michael Schultz from the University of Göttengen in Germany that appeared in the January 2004 American Journal of Physical Anthropology and the August 2005 issue of Biological Chemistry. In those papers, the researchers describe methods for extracting, solubilizing, and identifying growth factors in archeological bone.
 
Schmidt-Schultz and Schultz also were part of the team that worked on the IJC study. Schmidt-Schultz oversaw the proteomics work of that study. 
 
In the current study, the research team used SDS-PAGE, 2D electrophoresis, Western-blot analysis, along with macroscopic, endoscopic, radiological, light microscope, and scanning-electron microscopic techniques, to compare proteins extracted from the Iron Age ruler, who is estimated to have been between 40 and 50 years old when he died, with samples taken from a 62-year-old German with prostate cancer and a healthy 74-year-old German.
 
Researchers have been able to extract ECM proteins for the past 25 years using a technique developed by JD Termine and his colleagues in which proteins are taken from the supernatants after centrifugation steps.
 
However, for the IJC study, the authors used a technique that Schmidt-Schultz and Schultz developed to confirm the presence of prostate cancer in the king. The method, which is described in the 2004 American Journal of Physical Anthropology paper, differs from Termine’s technique in that the researchers “always work with the pellets. The supernatants were discarded, and we also solubilized the ECM proteins from the last lyophilized pellet.”
 

“… such investigations are interesting because certain types of cancer that these days are estimated to be characteristic of our own times and frequently described as being due to our western civilization are also found in antiquity.”

Once they extracted the ECM proteins, the researchers precipitated them with trichloracetic acid and separated them either by SDS-PAGE or 2D electophoresis. They then performed Western-blot analysis with specific antibodies to identify the proteins.
 
The authors were able to see positive bands in a Western blot for monoclonal antibodies against human prostate-specific antigen in biological samples from both the Scythian king and the 62-year-old prostate cancer patient, but not in the healthy 74-year-old.
 
While acknowledging that they had to use “special diagnostic criteria” to evaluate archaeological skeletal remains due to cellular and soft-tissue degradation, the authors found several characteristics in the king’s samples they say are similar to modern prostate cancer.
 
Usually, they say, prostate cancer results in the solidification or condensation of bone, but while other cancers may give rise to osteoblastic metastases, in which bony structures are formed, prostate carcinoma may also produce osteoclastic metastases, in which bone is destroyed. Macroscopically visible osteoblastic and osteoclastic legions were found throughout the Scythian ruler’s skeleton, and in some parts of his body there were “pronounced vestiges of an irregular rapid bone growth characterized by a primary osteoclastic and a secondary dominating osteoblastic process.”
 
For example, samples of cranial, rib, and vertebrae samples showed that a “bulky, almost compact structure” had replaced the original bone, causing a loss of the diploic modules of the red bone marrow.
 
The morphology and pattern of lesions found on the king’s skeleton are characteristic of carcinoma of the prostate, they said, and “in comparison with the recent cases, the micro-morphology of the product of the osteoblastic processes in the [Scythian king] is, indeed, the same.”
 
In prostate cancer, some molecules associated with the disease are transported by blood and absorbed by bone hydroxyapatite. These molecules were identified in the bone ECM of the Scythian ruler “even thousands of years after his death,” the researchers report.
 
They found high PSA levels in his bones, “and the ECM proteins are bound to apatite just as in living bone.” Because they did not degrade, unlike cell molecules such as DNA, “it is now possible to confirm the diagnosis of tumor diseases by specific tumor markers also in ancient specimens,” the authors said.
 
“This observation provides, for the first time, key insights into a reliable diagnosis of prostate carcinoma in ancient times, which give new impulse to models for the further studies in the field of the comparative evolution and the history of tumorous disease starting from ancient and leading up to modern times,” they said.

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