Figure 1
Micrometastasis progression in standard and diurnal cultures. Conceptual view of (top) micrometastasis progression in three-dimensional perfused liver microreactors maintained with controlled circadian profiles of key components of the portal circulation (nutrients, insulin) and the systemic circulation (cortisol) compared with (bottom) micrometastasis progression in standard culture with daily medium changes. Approximate relative values of diurnal fluctuations in the tissue microenvironment are shown for each case; absolute magnitudes of cortisol and insulin are conventionally supraphysiological in the standard culture. Micrometastases are created by seeding individual tumor cells within the parenchyma of the tissue mimic, where flow of oxygenated culture medium into the tissue supports survival and proliferation. Carcinoma cells may re-express cadherin and integrate into the tissue, or may exhibit unrestrained growth. As tumors grow, the tissue becomes hypoxic, stromal cells proliferate, and the mix of cytokines and acute phase proteins becomes altered. Parameters listed (nutrient and hormone levels, cytokine levels, oxygen) are measured noninvasively to assess the progression of metastases. A premise is that the uncontrolled metastases stimulated by supraphysiological levels of hormones and nutrients in standard culture will be easier to eradicate by traditional chemotherapeutic agents that target proliferation, and thus fail to represent the full spectrum of behaviors of clinically important metastases compared with the case of controlled diurnal stimulation. PO2, oxygen partial pressure.