During previous experiments it has been established that high activity of enzyme lysyl oxidase (LOX) may be responsible for mammary gland cancer spread. Only recently did it turn out that, blocking LOX, an extracellular matrix remodeling enzyme, can stop cancer cells from invading the surrounding tissue and metastasizing to faraway organs. Dr Janine Erler, team leader at the British Institute of Cancer Research, said that though the method has been tested only in vitro and on mice, “LOXL2 is a fantastic drug target, it’s highly likely to be used in a clinical setting (1).”
The molecular role of lysyl oxidase has been studied thoroughly after it was discovered that high levels of LOX, its improper localization and function are associated with malignant neoplasms. It turns out that the enzyme, which is vital for forming cross-links of collagen and elastin, is overexpressed in samples of breast cancer (2) as well as in squamous cell carcinomas (3), pancreatic carcinoma (4), uveal melanoma (5), cancers of the gastrointestinal tract (6),(7) and perhaps many other tumors. Lysyl oxidase seems to be a crucial enzyme for connective tissue metabolism, which can be explained by the fact that decreases in LOX expression are present in such inborn disorders as cutis laxa, Ehler-Danlos syndrome and Menkes’ syndrome. On the other hand increases in LOX activity play major role in development of frequent fibrotic diseases such as arteriosclerosis, scleroderma as well as liver and lung cirrhosis.
LOXL2 stands for lysyl oxidase-like 2 protein which is a homologue of classic lysyl oxidase and is particularly known for itˈs protumorigenic activity. Therefore for many years it has been considered as a possible therapeutic target in oncology. Firstly scientists thought about breast cancer prevention, but it has been estimated that LOXL2 did not promote any special migratory abilities (8) in normal breast epithelial cells, hence blocking it would not result in lesser risk of cancerogenesis. But some studies revealed that knocking down the enzyme in malignantly transformed cell lines by a monoclonal antibody or genetic engineering resulted in the reduction of the risk of metastasis (9). It may not seem a significant feature, but taking into consideration the fact that about 90% of cancer patient mortality is caused by metastasis it is clear that this discovery could change the survival rate of breast cancer sufferers.
The latest study, financed by the Breast Cancer Campaign and Cancer Research UK, was published in March in prestigious Cancer Research journal (10). It made use of the achievements of previous research and searched for a way to stop estrogen negative breast cancer from metastasizing. To great surprise, the results showed that when mice, which were genetically modified to develop breast tumours, were given D-penicillamine (an inhibitor of LOXL2), the primary mammary gland tumour grew at a comperable rate to the one in mice that had not received this treatment. Nevertheless they had fewer lung metastatic tumours. Protracting the treatment with D-penicillamine made no difference in cancer spread. To our disappointment this suggests that LOXL2 takes part only in the early stages of cancer invasion.
Studying the mechanisms of how neoplasms develop, researchers may encounter potential targets for cancer treatment. One of them is definitely lysyl oxidase like protein 2. Although the tests are still preliminary, involving mice model, for now it seems enough to believe, that for the first time stopping cancer spread is possible. Perhaps after the method is proved safe and beneficial for human organisms the fate of millions of women can be changed.
2. A molecular role for lysyl oxidase in breast cancer invasion. Kirschmann DA, Seftor EA, Fong SF, Nieva DR, Sullivan CM, Edwards EM, Sommer P, Csiszar K, Hendrix MJ. http://www.ncbi.nlm.nih.gov/pubmed/12154058
3.Lysyl oxidase-like 2 as a new poor prognosis marker of squamous cell carcinomas. Peinado H, Moreno-Bueno G, Hardisson D, Pérez-Gómez E, Santos V, Mendiola M, de Diego JI, Nistal M, Quintanilla M, Portillo F, Cano A. http://www.ncbi.nlm.nih.gov/pubmed/18559498
4. Functional analysis of LOXL2 in pancreatic carcinoma. Rückert F, Joensson P, Saeger HD, Grützmann R, Pilarsky C. http://www.ncbi.nlm.nih.gov/pubmed/20012301
5. Lysyl oxidase expression and inhibition in uveal melanoma. Abourbih DA, Di Cesare S, Orellana ME, Antecka E, Martins C, Petruccelli LA, Burnier MN Jr. http://www.ncbi.nlm.nih.gov/pubmed/20179655
6. Lysyl oxidase-like 2 expression is increased in colon and esophageal tumors and associated with less differentiated colon tumors. Fong SF, Dietzsch E, Fong KS, Hollosi P, Asuncion L, He Q, Parker MI, Csiszar K. http://www.ncbi.nlm.nih.gov/pubmed/17394133
7. Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway. Peng L, Ran YL, Hu H, Yu L, Liu Q, Zhou Z, Sun YM, Sun LC, Pan J, Sun LX, Zhao P, Yang ZH. http://www.ncbi.nlm.nih.gov/pubmed/19625348
8. Lysyl oxidase-like 2 promotes migration in noninvasive breast cancer cells but not in normal breast epithelial cells. Hollosi P, Yakushiji JK, Fong KS, Csiszar K, Fong SF. http://www.ncbi.nlm.nih.gov/pubmed/19330836
9. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment.Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, Oyasu M, Mikels A, Vaysberg M, Ghermazien H, Wai C, Garcia CA, Velayo AC, Jorgensen B, Biermann D, Tsai D, Green J, Zaffryar-Eilot S, Holzer A, Ogg S, Thai D, Neufeld G, Van Vlasselaer P, Smith V. http://www.ncbi.nlm.nih.gov/pubmed/20818376
10. LOXL2-Mediated Matrix Remodeling in Metastasis and Mammary Gland Involution. Barker HE, Chang J, Cox TR, Lang G, Bird D, Nicolau M, Evans HR, Gartland A, Erler JT. http://www.ncbi.nlm.nih.gov/pubmed/21233336