Cancer researchers at Jefferson Medical College, Philadelphia, are gathering further evidence that damage to the human retinoblastoma-related gene, Rb-2/p130, a powerful tumor-suppressor, may lead to lung cancer.
They had previously suggested that damage to the Rb gene from cigarette smoke, air pollution and other toxins may lead to lung cancer. Such damage prevented the gene from making a key protein, pRb-2/p130, which suppresses tumor formation. They also saw evidence that levels of the protein correlated with tumor aggressiveness. This new work strengthens that finding.
“We looked at 158 lung cancer patient samples, and saw a strong correlation between low levels of the protein and aggressive and metastasizing lung cancer,” said Antonio Giordano, M.D., Ph.D., associate professor of pathology, anatomy, and cell biology, who led the work.
The research may lead to a new lung cancer tumor-grading test to enable physicians to determine how much Rb-2/p130 protein is found in individual lung cancer patients. This information can help physicians begin treatments earlier, and tailor them to specific patients, depending on how aggressive the cancer is.
“Now a tumor grading test is much closer to reality,” said Giordano, who is also president of the Sbarro Institute for Cancer Research and Molecular Medicine, which is affiliated with the college.
Of particular importance, he noted, was the strong relationship between protein levels and the amount that the cancer spread. "We not only found the confirming relationship between aggressiveness of the tumor and decreasing Rb2 protein, but also with the degree of metastasis," he said. Giordano and his colleagues at Jefferson and at the Second University of Naples report their findings in the October issue of Clinical Cancer Research..
The researchers monitored the expression of the Rb2 gene, which is a normal gene and is expressed in all tissues, in normal cells. They showed that two Rb-2/130 proteins, pRb-2/130 and p107, are ubiquitous throughout the body’s tissues and play vital roles in cell growth control. The p107 protein is found in high levels in breast and prostate tissue. The pRb-2 protein is present in high amounts in normal lung cells. Yet when Rb-2/p130 is altered and cannot produce pRb-2, the cell may not reach its normal stage of programmed death. It continues to divide, leading to cancer.
Last July, reporting in Clinical Cancer Research, Giordano’s team described a study of 77 tumor samples from patients with surgically resected lung cancer. Similarly, they found that the less pRb-2/p130 protein expressed in a tumor, the more aggressive the lung cancer is. In related research reported in the August issue of Nature Medicine, Giordano's team found direct evidence of a potential monkey virus mechanism behind the development of mesothelioma, a rare connective-tissue cancer commonly associated with asbestos exposure. The virus rendered key tumor-suppressor genes ineffective. The finding was particularly significant, Giordano said, because of the different mechanism potentially involved in causing cancer. In the case of mesothelioma, the body’s tissue levels of the pRb-2 protein remained normal; the protein merely did not perform its job. In contrast, protein levels in lung cancer tissue are much lower than normal.
According to Giordano, the first type of test to be developed will accurately describe the stage of cancer--either I, II, III, or IV--of an individual, based on the levels of protein in the lung cancer tumor.
Another potential test aims to analyze Rb-2/p130 protein to determine genetic susceptibility. Still another test being studied involves using Rb-2/p130 protein as a tumor marker to learn when patients have developed lung cancer.
Lung cancer is notoriously difficult to treat. The earlier the disease can be diagnosed, the better the chances are of providing helpful treatment.
"The goal is provide early diagnosis to monitor susceptible people who will develop the disease," Giordano said. "We’d like to design alternative therapeutic strategies to combat lung cancer, including finding a target for [future efforts in] gene therapy.
"In order to have some therapeutic value, a test needs to be developed that is cheap and accessible to everyone," he explained. "We would like to run prospective studies as well to be able to anticipate in some patients when cancer might develop."
Because he has proven the Rb2 gene is ubiquitous throughout the body’s tissues and organs, he believes that the work may have applications to similar diagnostic tests for other cancers, such as breast, ovarian and endometrial. "The work will open up an avenue and provide an indication to researchers and physicians . . . that Rb2 is important to the function of different cell types in the body."
Giordano also hopes to gain a better understanding of how the damaged Rb gene causes cancer.
"The goal is improved diagnosis, detecting people who will develop disease, and ultimately design alternative and specific therapeutic strategies. This can be done only by understanding how this mechanism of cancer development works."
Journal
Clinical Cancer Research