Abstract
Tumor latency and dormancy are obstacles to effective cancer treatment. In brain metastases, emergence of a lesion can occur at varying intervals from diagnosis and in some cases following successful treatment of the primary tumor. Genetic factors that drive brain metastases have been identified, such as those involved in cell adhesion, signaling, extravasation, and metabolism. From this wealth of knowledge, vexing questions still remain; why is there a difference in strategy to facilitate outgrowth and why is there a difference in latency? One missing link may be the role of tissue biophysics of the brain microenvironment in infiltrating cells. Here, I discuss the mechanical cues that may influence disseminated tumor cells in the brain, as a function of age and disease. I further discuss in vitro and in vivo preclinical models such as 3D culture systems and zebrafish to study the role of the mechanical environment in brain metastasis in an effort of providing novel targeted therapeutics.
Highlights
Solid cancers often show preferential organ colonization in line with Paget’s original seedsoil hypothesis, based on his examination of breast cancer patients at autopsy.[1,2] Paget likened tumor cells to “seeds” and the organ of eventual secondary lesion as the “soil.” Paget hypothesized that the establishment of a de novo lesion is achieved only if there is compatibility between seed and soil.[1]
Metastatic brain lesions account for $90% of all central nervous system (CNS) tumors, outnumbering primary brain tumors at a factor of $10:1.5,6 Of all sites of organ colonization, brain metastases are associated with the worst prognosis, with a median survival of less than a year on average, coupled with a reduced quality of life due to associated physical and cognitive deficits.[7,8]
Intrinsic differences in genes and signaling pathways that regulate organ specificity have been evaluated using murine models where metastasis is evaluated at the time point of relatively mature lesions.[12,80,151,152]
Summary
Solid cancers often show preferential organ colonization in line with Paget’s original seedsoil hypothesis, based on his examination of breast cancer patients at autopsy.[1,2] Paget likened tumor cells to “seeds” and the organ of eventual secondary lesion as the “soil.” Paget hypothesized that the establishment of a de novo lesion is achieved only if there is compatibility between seed and soil.[1]. Avascular growth occurs when tumor cells co-opt existing vessels, proliferating and migrating along the abluminal surfaces.[20,21] The latter strategy is the one in which tumor cells that have invaded tissue parenchyma create new vasculature to enable continued proliferation, invasion, and successful expansion beyond a tumor volume of $1–2 mm3.9,19 Jain et al present an excellent review on the cytokines and cellular mechanisms that govern angiogenesis in the brain for further examination.[22]. There is a relatively low amount of fibrillar proteins such as collagen type I, fibronectin, and vitronectin within the ECM microenvironment.[28,30] These in addition to basement membrane proteins, such as laminin, are largely restricted to the vascular and perivascular spaces in the brain.[7,30]. In the case of vascular co-option, the topography of blood vessels provides signals to surrounding tumor cells that invade and proliferate within the brain parenchyma, which can all be influenced by the local tissue mechanics. 031801-4 Kandice Tanner in cancers that originate in the brain has been studied; such as an increase in tissue stiffness is observed in high grade glioma.[27,35] the effect of the mechanical environment on infiltrating tumor cells remains largely unknown
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