ALDH Activity Correlates with Metastatic Potential in Primary Sarcomas of Bone

Abstract

Osteosarcoma (OS), chondrosarcoma (CSA), and Ewings sarcoma (ES) are the most common primary malignancies of bone, and are rare diseases. As with all sarcomas, the prognosis of these diseases ultimately depends on the presence of metastatic disease. Survival is therefore closely linked with the biology and metastatic potential of a particular bone tumor’s cells. Here we describe a significant correlation of aldehyde dehydrogenase (ALDH) activity and the presence/absence of distant metastases in ten consecutive cases of human bone sarcomas. Additionally, cultured human CSA cells, which are historically chemo- and radio-resistant, may be sensitive to the ALDH inhibitor, disulfiram. While it is premature to draw broad conclusions from such a small series, the importance of ALDH activity and inhibition in the metastatic potential of primary bone sarcomas should be investigated further.

Cancer stem cells in osteosarcoma

“…A subpopulation of ALDH1 high MG63 cells was detected by Honoki et al (25) who further reported ALDH1 high cells to have increased expression of stem-like genes (Nanog, Oct3/4, Stat3, Sox2), higher resistance to doxorubicin and cisplatin and increased self-renewal ability as shown by sphere formation. Importantly, ALDH high cells were also detected in human osteosarcoma samples and increased ALDH activity was further correlated to metastatic potential (26). It was also shown that inhibition of ALDH activity using disulfiram resulted in reduced cell proliferation suggesting direct targeting of CSC phenotype cells.…”

The Use of Molecular Pathway Inhibitors in the Treatment of Osteosarcoma

“…ALDH expression also appears to be linked with metastatic potential. Semisolid matrigel matrix invasion assays showed a correlation between ALDH levels and increased invasiveness when comparing two murine OS cell lines [7]. OS cells treated with disuliram, an ALDH-inhibitor, show reduced ALDH expression and altered cellular morphology, with fewer invadopodia and greater shape uniformity [6,15,16].…”

“…Aldehyde dehydrogenases (ALDHs) are a superfamily of nicotinamide adenine dinucleotide phosphate (NADP + )-dependent tetrameric enzymes that participate in aldehyde metabolism via catalysis of exogenous and endogenous aldehydes into their corresponding carboxylic acids and the cell's resistance to oxidative stress [4][5][6][7]. Inhibition of ALDH can lead to a buildup of aldehydes that can lead to toxic side-efects, which include enzyme inactivation, DNA damage, impairment of cellular homeostasis, and cell death by forming adducts with various cellular targets [4,8,9].…”

“…ALDH has, therefore, been implicated as a potential CSC marker. Cells found to be high in ALDH have demonstrated enhanced tumorigenicity in multiple cancers [7]. Elevated ALDH levels have been associated with poor survival in patients with breast and ovarian cancers [13,14].…”

Lymph node metastasis of osteosarcomas

“…Эпителиальный мембранный антиген регулярно экспрессируется в хордоме [43]. [44,45]. О разнообразных формах проявле-ния «эпителиальных» качеств остеосаркомы свидетель-ствуют многочисленные публикации -описаны как эпи-телиоидные варианты опухоли с образованием плоскокле-точных жемчужин с гландулярным компонентом, так и морфологически типичные остеосаркомы с эпителиаль-ным иммунофенотипом [4,43,46].…”