Estrogen matters in metastasis

Metastatic cancer cells meet several physical, biochemical and immunological barriers before colonizing a new territory. Cancerous cells turn invasive, mobile and eventually disengage from their native niche. This is followed by their intravasation, extravasation, survival, proliferation, and colonization into distant organs. Unlike well-confined tumors, which respond favorably to anti-cancer therapeutics, metastatic tumors are life-threatening and incurable. More than 90% of cancer-related mortality is caused by metastases, hence the emphasis is now on developing the strategies to block or reverse the process of metastasis. This has ensued intensive research with a focus on the mechanisms underlying metastasis. Substantial work carried out in this direction has led to the identification of specific enzymes, proteins, cytokines, chemokines, growth factors, exosomes, miRNA and lipids, etc. as the facilitators of metastasis. Metastatic cells are exposed to a diverse array of local and systemic signals. Among these, estrogens are of great relevance. Estrogens have been strongly linked to cancers, especially of breast and uterine origin. Recent data hint that estrogens, well recognized for their role in proliferation, may have a role in metastasis also. It is proposed that influence of estrogen on metastasis may be independent of its proliferation-inducing ability. Data are emerging to suggest that estrogens have potential to modulate various events of the metastatic cascade such as local invasion, intravasation, anoikis, immune evasion, extravasation, angiogenesis and metastatic colonization. This review summarizes some of the recent advances in our knowledge on the role of estrogens in the metastatic cascade of cancerous cells.