SOLID STRESS INHIBITS THE GROWTH OF MULTICELLULAR TUMOR SPHEROIDS

In normal tissues, the processes of growth, remodeling, and morphogene sis are tightly regulated by the stress field; conversely, stress may be generated by these processes. We demonstrate that solid stress inhi bits tumor growth iii vitro, regardless of host species, tissue of ori gin, or differentiation state. The inhibiting stress for multicellular tumor spheroid growth in agarose matrices was 45 to 120 mm Hg. This s tress, which greatly exceeds blood pressure in tumor vessels, is suffi cient to induce the collapse of vascular or lymphatic vessels in tumor s in vivo and can explain impaired blood flow, poor lymphatic drainage , and suboptimal drug delivery previously reported in solid tumors. Th e stress-induced growth inhibition of plateau-phase spheroids was acco mpanied, at the cellular level, by decreased apoptosis with no signifi cant changes in proliferation. A concomitant increase In the cellular packing density was observed, which may prevent cells from undergoing apoptosis via a cell-volume or cell-shape transduction mechanism. Thes e results suggest that solid stress controls tumor growth at both the macroscopic and cellular levels, and thus influences tumor progression and delivery of therapeutic agents.