Solid stress inhibits the growth of multicellular tumor spheroids

Abstract

In normal tissues, the processes of growth, remodeling, and morphogenesis are tightly regulated by the stress field; conversely, stress may be generated by these processes. We demonstrate that solid stress inhibits tumor growth in vitro, regardless of host species, tissue of origin, or differentiation state. The inhibiting stress for multicellular tumor spheroid growth in agarose matrices was 45 to 120 mm Hg. This stress, which greatly exceeds blood pressure in tumor vessels, is sufficient to induce the collapse of vascular or lymphatic vessels in tumors in vivo and can explain impaired blood flow, poor lymphatic drainage, and suboptimal drug delivery previously reported in solid tumors. The stress-induced growth inhibition of plateau-phase spheroids was accompanied, at the cellular level, by decreased apoptosis with no significant 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. These 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.

Solid stress facilitates spheroid formation: potential involvement of hyaluronan

“…In 1.8% agarose gels the growth is completely arrested. We suggest that this inhibition in growth results from increasing stress as trapped spheroids grow within denser gels, consistent with our previous data on five different cell lines: LS174T (human colon adenocarExperimental Therapeutics cinoma), MCaIV (murine mammary carcinoma), and the clones (A, B, C) of a rat rhabdomyosarcoma, BA-HAN-1 (Helmlinger et al, 1997a). Unlike our previous study, we found that the specific growth rate, a, decreased with increasing gel concentration for AT2.1 (P=0.023), but not for AT3.1 ( Figure 2C).…”

“…Similar to our previous findings (Helmlinger et al, 1997a), the AT2.1 spheroids retained their morphology and resumed their growth as in free suspension (Figure 3). The AT3.1 cells also retained their morphology for the first several days, but lost their integrity by days 6 -8 and disintegrated into a loose collection of cells.…”

“…By growing neoplastic cells as spheroids in agarose gels (Sutherland, 1988), we have recently measured the solid (mechanical) stress generated by these cells during growth (Helmlinger et al, 1997a). We have shown that this stress inhibits the growth of spheroids and that this growth-inhibiting stress is in the range of 45 to 120 mmHg.…”

A Hybrid Model of Tumor–Stromal Interactions in Breast Cancer

“…Once the space is filled near the origin of TECs, TECs begin to feel a reciprocal tissue resistance force from the surrounding stromal tissue and tend to grow in the longitudinal direction, i.e., in the direction of less stress. This is qualitatively consistent with experimental results described earlier on anisotropic growth (Helmlinger et al 1997;Cheng et al 2009). Figure 20(H) shows the time course of the tumor population for both cases in (F) and (G) above.…”

“…Parameter PRCC\ k Parameter PRCC\ k other tumor types that the surrounding medium affects growth of tumor spheroids (Helmlinger et al 1997;Cheng et al 2009). Transformed mammary epithelial cells may also respond to stresses by increasing FGF and VEGF signaling to promote their proliferation and by increasing production of MMPs to promote invasion (Paszek and Weaver 2004).…”