Why does Jack, and not Jill, break his crown? Sex disparity in brain tumors

Abstract

It is often reported that brain tumors occur more frequently in males, and that males suffer a worse outcome from brain tumors than females. If correct, these observations suggest that sex plays a fundamental role in brain tumor biology. The following review of the literature regarding primary and metastatic brain tumors, reveals that brain tumors do occur more frequently in males compared to females regardless of age, tumor histology, or region of the world. Sexually dimorphic mechanisms that might control tumor cell biology, as well as immune and brain microenvironmental responses to cancer, are explored as the basis for this sex disparity. Elucidating the mechanisms by which sex chromosomes and sex hormones impact on brain tumorigenesis and progression will advance our understanding of basic cancer biology and is likely to be essential for optimizing the care of brain tumor patients.

Figure 1

Sex-based differences in the rates of primary brain tumor exist regardless of age or geographical location. Reports from around the world describing the incidence of common brain tumors as a function of sex are identified and linked to their countries of origin. Numbers shown in the parentheses are the sex ratio (male/female) of major primary brain tumor types extracted from 16 independent publications from 15 countries, including all major continents and regions of the world (North America, South America, Europe, Middle East, Africa, Asia and Oceania) except for Antarctica. Overall, these studies covered the period of 1974 to 2008, and the sex ratio (male/female) in almost all major brain tumors including both malignant and benign tumors is greater than 1 with a range of 1 to approximately 3.5. See also [2,10-24]. Abbreviations: AST = astrocytoma; EPD = ependymoma; GBM = glioblastoma (multiforme); Glioma, (NOS) = glioma, not otherwise specified; MB = medulloblastoma; OLG = oligodendroglioma; PA = pilocytic astrocytoma.

Figure 2

The mechanisms of sexual differentiation overlap with the mechanisms of oncogenesis. The process of sexual differentiation shares many fundamental features with oncogenesis, including changes in DNA methylation, glucose metabolism, growth factor signaling, cell migration, proliferation, apoptosis and differentiation.

Figure 3

Potential mechanisms for disparate rates of brain metastases in males and females. The process of metastasis to the brain involves distinct steps dependent on different genes, pathways and mechanisms. The initial stage (1) involves tumor cell intrinsic mechanisms for the degradation of the extracellular matrix and activation of migratory pathways. This process is often referred to as epithelial to mesenchymal transition (EMT). Pictured is a lung cancer primary tumor and the hematogenous dissemination of lung cancer cells. For metastases to the brain, cells that gain access to the circulatory system and avoid natural killer (NK) cell deletion must cross the blood brain barrier (2). Once present in the brain parenchyma, the lung cancer cells must condition the brain microenvironment for continued growth (3). This process involves secretion of cytokines that induce a microenvironmental response. Pictured is the action of the lung cancer cells on an astrocyte. (4) The activated astrocytes secrete cytokines and growth factors such as interleukin (IL)-6 that promote tumor growth and protect secondary tumors from the cytotoxic effects of chemotherapy.