**3. Conclusion**

86 Malignant Mesothelioma

estrogens. The human CYP19A1 gene, located in the 21.2 region on the long arm of chromosome 15 (15q21.2), spans a region that consists of a 30 kb coding region and a 93 kb regulatory region. Its regulatory region contains at least 10 distinct promoters regulated in a tissue- or signalling pathway-specific manner. Each promoter is regulated by a distinct set of regulatory sequences in DNA and transcription factors that bind to these specific sequences. These partially tissue-specific promoters are used in the gonads, bone, brain, vascular tissue, adipose tissue, skin, foetal liver, and placenta for estrogen biosynthesis necessary for human physiology (Bulun et al., 2004). Estrogens contribute to differentiation and maturation in normal lung (Patrone et al., 2003) and also stimulate growth and progression of lung tumors (Stabile et al., 2002; Pietras et al., 2005). Two major pathways, generally termed genomic and

**Figure 4.** Estrogen Receptor fuction: Genomic (Nuclear ER) and Non Genomic (Membrane ER) action

Estradiol has traditionally been described to mediate its effects via intracellular receptors located in the cytoplasm or on the nuclear membrane and thus studies have investigated the effect of estradiol on transcription factors in the regulation of target genes . Estradiol also acts on the plasma membrane to initiate signaling pathways in the cytoplasm and regulate cellular functions, which is called the non-genomic pathway (Simoncini et al., 2004; Simoncini & Genazzani, 2003). PGE2 is thought to be an important regulator of CYP19A1 gene expression (Zhao et al., 1996). PGE2 increased CYP19A1 activity level in MM cell lines (Stoppoloni et al., 2011). Over the last decade many studies have been carried out to identify potential CYP19A1 stimulatory factors: IL-6 was the most potent factor detected that could stimulate CYP19A1 activity (Reed et al., 1992). The MM cell lines were capable of releasing a constitutively high amount of IL-6 (>1,100 pg.mL supernatant-1 of confluent cultures) (Orengo et al., 1999). This could explain the presence of CYP19A1 in MM cells. Furthermore, estrogen receptor (ER) were also detected in MM cell lines by western blot. The classic 67 kDa and a variant 46 kDa of ERα and 59 kDa of ERβ were expressed in MM cell lines. In support of these results there are recent literature data pointing to a role for estrogens in MM pathogenesis. Epidemiologic studies have identified female gender as a positive prognostic factor for MM (Pinton et al., 2009), although no experimental explanation of this

non-genomic, are known to mediate estradiol effects on cells. (Fig.4)

COX-2, EGFR and CYP19A1 are investigational at the present time. The cross-talk between markers that have been described and their value as prognostic indicators will need to be validated in prospective studies in larger patient populations. Their role at the present time is to give us direction towards development of newer therapies in this very resistant tumor. The standard of care at the present time for malignant mesothelioma does not involve checking for these markers and making patient care decisions based on them. But we hope that in the near future this would become a reality with a better treatment approach and prognosis for these patients. Furthermore the possibility of using natural anti-inflammatory products in the chemoprevention of people at risk of MM can not exclude.

## **Author details**

Rossella Galati *Regina Elena Cancer Institute, Rome, Italy* 
