Role of the basement membrane in tumor cell dormancy and cytotoxic resistance

Objectives and Methods: Tumor dormancy and resistance to cytotoxic agents a re key limiting events in the treatment of malignant diseases. To determine whether both are influenced by the extracellular milieu in which tumors re side, HT1080 human fibrosarcoma, MCF-7 breast carcinoma and OSCORT osteosar coma cell proliferation, viability, apoptosis a nd cyto reductive-treatment -induced death were investigated in the presence or absence of extracellula r matrix (ECM). Results: ECM-adherent, but not plastic-adherent HT1080 cell s formed a multicellular network accompanied by reduced proliferation and l owered DNA synthetic capacity. The number of cells in S-phase was dramatica lly reduced. Viable cells entered a state of dormancy reminiscent of that o bserved in the step of metastasis after extravasation, i.e. prior to the in itiation of progressive growth. Such ECM-induced dormancy could be reversed by plating cells on plastic, but only after a 48-hour lag period. No diffe rence was indicated in clonogenicity of HT1080 cells originated from plasti c or ECM gel. However, the cells released from ECM gel showed significantly reduced migration ability. The resistance of anchored cells against cytoto xic damage was increased by ECM gel. Examination of cytoreductive treatment revealed that ECM adherence at the time of injury is partially protective, a property which was also moderately apparent when injured cells were tran sferred to the basement membrane. Conclusions: Taken together, these result s suggest that the ECM plays a key role in tumor dormancy and cytotoxic res istance, both explorable at the molecular level using our in vitro model sy stem. Copyright (C) 2001 S. Karger AG, Basel.