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.

[Rich66]

So it sounds like they need to find a way to elicit or bolster(transfect?) the KISS1 receptor? Could give real hope to those with mets..but not those with teenagers.

[Rich66]

Danny Welch, Ph.D.




Professor of Pathology
Senior Scientist - Comprehensive Cancer Center, Center for Metabolic
Bone Disease, Cell Adhesion and Matrix Research Center, Gene Therapy Center

Education:
B.S. in Biological Sciences from the University of California at Irvine;
Ph.D. in Biomedical Sciences from The University of Texas at Houston

Awards/Recognitions:
American Cancer Society Chairman's Award; Sigma Xi Scientific Research
Society;National Cancer Institute, Department of Defense, Susan G. Komen
Breast Cancer Research Foundation, National Foundation for Cancer
Research

Research Interests:
Cancer Biology. The major cause of cancer deaths is the ability of tumor cells to spread to distant organs, a process termed metastasis. Metastasis is the ultimate step in a tumor cells progression toward autonomy from the host. Our goal is to determine the mechanisms by which tumor cells acquire the ability to metastasize. We know that two basic cellular changes are involved: turning on metastasis promoters and turning off metastasis suppressors. Our laboratory has focused on metastasis suppressors and we have cloned four of them KISS1, BRMS1, TXNIP and CRSP3. When cells are engineered to re-express metastasis suppressors, metastasis is suppressed without blocking tumor formation. The current focus of the lab is to understand the mechanisms by which these molecules block metastasis.

Based upon differential growth of tumor cells at orthotopic sites (i.e., mammary fat pad for breast cancers; intradermal for melanoma, etc.) compared to the sites of metastatic colonization, it is clear that metastasis suppressors are altering how tumor cells interact with the surrounding microenvironment. They can do this at multiple cellular levels. BRMS1 appears to be acting at the level of gene transcription (i.e., it is interacting with members of the histone deacetylase complex) to affect signaling via the phosphoinositide pathways and via NFkappaB. CRSP3, TXNIP and KISS1 appear to form a pathway for metastasis suppression in human melanoma; however, downstream effectors are not yet defined.

Keeping the them of tumor cell interactions with the microenvironment, another project in the lab involves determining how breast cancers home to bone (i.e., the most common site of breast cancer spread is to the bones.). We have developed fluorescent models of breast cancer which allows us to detect single cells inside a bone without having to use histology. Using these models, we have recently demonstrated that breast carcinoma cells enter the bone and manipulate normal bone homeostasis by killing osteoblasts. Current studies involve dissecting the mechanisms by which tumor cells induce osteoblast apoptosis.

This lab offers the opportunity to study tumor cell biology from the DNA level through the in vivo level. We use molecular biology, biochemistry, cell culture and animals to address the issues raised above. The laboratory is also highly interactive, team oriented and collaborative. We have ongoing collaborations with other research groups from UAB, Penn State, Mass General, U. Chicago, National Cancer Institute, Cleveland Clinic and Utah State. In short, we believe that these research projects will lead to a more complete understanding of the fundamental mechanisms underlying tumor progression. Moreover, novel, effective treatments will result from this research.


Selected Publications:

Seraj, M.J.*, Samant, R.S.*, Verderame, M.F., Welch, D.R. (2000) Functional evidence for a novel human breast carcinoma metastasis suppressor, BRMS1, encoded at chromosome 11q13 * Contributed equally to this work. Cancer Research 60: 2764-2769.

Shevde-Samant, L.A. and Welch, D.R. (2003) Metastasis suppressor pathways an evolving paradigm. Cancer Letters 198: 1-20.

Meehan, W.J., Samant, R.S., Hopper, J.E., Carrozza, M.J., Shevde, L.S., Workman, J.L., Eckert, K.E., Verderame, M.F. and Welch, D.R. (2004) Interaction of the BRMS1 metastasis suppressor with RBP1 and the mSin3 histone deacetylase complex. Journal of Biological Chemistry 279: 1562-1569.

Harms, J.F., Welch, D.R., Samant, R.S., Shevde, L.A., Miele, M.E., Babu, G.R., Goldberg, S.F., Gilman, V.R., Sosnowski, D.M., Campo, D.A., Gay, C.V., Budgeon, L.R., Mercer, R., Jewell, J., Mastro, A.M., Donahue, H.J., Erin, N., Debies, M.T., Meehan, W.J., Jones, A.L., Mbalaviele, G., Nickols, A., Christensen, N.D., Melly, R., Beck, L.N., Kent, J., Rader, R.K., Kotyk, J.J., Pagel, M.D., Westlin, W.F., Griggs, D.W., (2004) A small molecule antagonist of the _v3 integrin suppresses MDA-MB-435 skeletal metastasis. Clinical and Experimental Metastasis 21: 119-128.

DeWald, D.B., Torabinejad, J. Samant, R.S., Johnston, D., Erin, N., Shope, J.C., Xie, Y., Welch, D.R. (2005) Metastasis suppression by BRMS1 involves reduction of phosphoinositide signaling in MDA-MB-435 breast carcinoma cells. Cancer Research 65: 713-717.

Cicek,M., Fukuyama, R., Welch,D.R., Sizemore, N., Casey, G. (2005) Breast cancer metastasis suppressor (BRMS1) inhibits gene expression by targeting NFB activity. Cancer Research 65: 3586-3595.

Phadke, P.A., Mercer, R.R., Harms, J.F., Jia, Y., Kappes, J.C., Frost, A.R., Jewell, J.L., Bussard, K.M., Nelson, S., Moore, C., Gay, C.V., Mastro, A.M., Welch, D.R. (2006) Kinetics of metastatic breast cancer cell trafficking in bone. Clinical Cancer Research (In press).


Danny R. Welch, Ph.D.
UAB Address: Volker Hall G019B
Phone: (205) 934-2956
Fax: (205) 975-1126
E-mail: danwelch@uab.edu

[Rich66]

1: J Cell Biochem. 2009 Jun 16. [Epub ahead of print] Links

KiSS1 suppresses TNFalpha-induced breast cancer cell invasion via an inhibition of RhoA-Mediated NF-kappaB activation.

Cho SG, Li D, Stafford LJ, Luo J, Rodriguez-Villanueva M, Wang Y, Liu M.
Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030.
Tumor necrosis factor-alpha (TNFalpha) induces cancer development and metastasis, which is prominently achieved by nuclear factor-kappa B (NF-kappaB) activation. TNFalpha-induced NF-kappaB activation enhances cellular mechanisms including proliferation, migration, and invasion. KiSS1, a key regulator of puberty, was initially discovered as a tumor metastasis suppressor. The expression of KiSS1 was lost or down-regulated in different metastatic tumors. However, it is unclear whether KiSS1 regulates TNFalpha-induced NF-kappaB activation and further tumor cell migration. In this study, we demonstrate that KiSS1 suppresses the migration of breast cancer cells by inhibiting TNFalpha-induced NF-kappaB pathway and RhoA activation. Both KiSS1 overexpression and KP10 (kisspeptin-10) stimulation inhibited TNFalpha-induced NF-kappaB activity, suppressed TNFalpha-induced cell migration and cell attachment to fibronectin in breast cancer cells while KP10 has little effect on cancer cell prolife