Puberty Promoter (KISS1) May Also Suppress Breast Cancer Metastasis

[Rich66]

Puberty Promoter May Also Suppress Breast Cancer Metastasis

Elsevier Global Medical News. 2009 Apr 14, N Osterweil

PHOENIX (EGMN) - A product of the KISS1 gene, which is a powerful promoter of the explosive growth and tissue development of puberty, shows strong therapeutic promise as a suppressor of tumor metastasis.
Preclinical studies suggest that using the KISS1 products known as kisspeptins to block steps late in the metastatic cascade has the potential to have a significant beneficial effect on the survival of patients with metastatic disease, said Danny R. Welch, Ph.D., at a symposium of the Society of Surgical Oncology.
"My laboratory and many others are beginning to think that metastasis is a more tractable therapeutic target than had been previously believed," said Dr. Welch, professor of cell biology at the University of Alabama at Birmingham.
KISS1 or its productsappear to prevent a final step in metastasis, that of colonization of secondary sites where metastatic cells can grow, he explained. "The notion of KISSand anticolonization is that we might be able to achieve a happy medium, in which we hold the cells in a dormant state," he said. "It doesn't cure, but it prolongs, and it gives more opportunity for skilled hands such as yours to deal with the metastases that survive."
He defines metastasis as "the dissemination of neoplastic cells to discontinuous nearby or distant secondary or higher order sites where they proliferate to form a macroscopic mass of greater than 50 cells." He chose the 50-cell limit because of research suggesting that six or seven cell divisions are necessary to demonstrate clonality, he added. Metastases can be disseminated by a hematogenous process (perivascular spread), through the lymph system (as with most carcinomas), or across body cavities (as can occur with ovarian and bladder cancers). But Dr. Welch maintains that metastasis is a distinctly different process from tumorigenesis, invasive cancer (which occurs by direct extension to surrounding tissues), epithelial-to-mesenchymal transition, or dissemination of cells.
Metastasis-suppressors are sets of genes and molecules that, as the name states, suppress metastasis, but unlike tumor suppressors, they do not block the growth of the primary tumor, he said. There are now 25 known metastasis suppressors, and at least 5 others have been characterized, with the research findings currently in press.
KISS1 is processed into kisspeptins (one of which Welch's lab has dubbed KISS1, after the parent gene). It has been shown by Dr. Welch's group and others that in tumors where KISS1 is present, metastasis decreases and overall survival increases; this is true for melanoma, uveal melanoma, choriocarcinoma, and cancers of the esophagus, thyroid, stomach, pancreas, ovaries, endometrium, breast, and bladder. Paradoxically, a higher KISS1expression in hepatocellular carcinoma is associated with a worse prognosis, for reasons that are unclear.
Even more paradoxically, "its normal role in biology has nothing to do with cancer; [rather,] it's the master regulator of puberty," Dr. Welch said. He joked that teens, like metastatic cancer, "grow uncontrollably, don't respond to authority, congregate in places where they're not supposed to, and do not appreciate anything you tell them."
Although Dr. Welch and his colleagues initially could not pinpoint where in the metastatic cascade KISS1works, they saw it in action in an experimental model of metastasis. They took human melanoma cells, some of which were transfected to express KISS1, and injected them intravascularly into mice. The non-KISS1-expressing cells migrated to the lungs and killed the mice within 5-6 weeks.
"But the KISS-expressing cells arrive in the same proportion, and survive as single cells up to 9 months. The animals survive just fine. If we remove the primary tumors from these animals, they will survive for up to a year," Dr. Welch said.
Interestingly, when the KISS-transfected cells were harvested from the lung, grown in cell culture, and injected under the skin, a tumor would form at the same rate as it would when nontransfected tumor cells were injected. The KISS-expressing cells then migrated back to the lung, where they again remained dormant for extended periods.
"This one experiment shows that KISS1 allows every step of the metastatic cascade except growth at the secondary site," Dr. Welch said.
The investigators are currently working under the hypothesis that the presence of a KISS1 receptor is necessary for the antimetastatic effects, and that the receptor is expressed differentially depending on the tumor environment.