DEVELOPMENTAL STAGES IN EXPERIMENTAL LIVER METASTASES - RELATION TO INVASIVENESS

We have previously reported that an invasive morphotype can be evoked in a rat colon carcinoma by transplanting it into pre-induced subcutan eous granulation tissue. We have now studied the interaction of the sa me tumor with liver tissue, which is extremely poor in connective tiss ue in comparison with the subcutaneous site. Tumor cells were injected into the portal system and the resulting experimental liver metastase s were examined by electron microscopy and immunohistochemistry. Early metastases consisted of well-differentiated acini, fully surrounded b y connective tissue that was derived from the periportal stroma. In a later stage, this connective tissue was overgrown by tumor cells and, almost immediately, acinar differentiation was lost. Most metastases e ventually reached the liver capsule, which reacted by forming a layer of granulation tissue. Only in this layer, we observed invasion by thi n tumor cell strands, which were often intimately associated with fibr oblasts or with blood capillaries. The tumor cells remained smooth and rounded during this process. After fully penetrating the granulation tissue, the tumor cell strands reached the liver surface, where they f ormed poorly structured papillary masses that were nearly devoid of st roma. Our observations indicate that, even in a relatively homogeneous organ like the liver, the tumor-host interaction is highly complex an d dynamic. They also confirm the notion that granulation tissue stimul ates tumor invasiveness. Finally, they show that tumor cells can activ ely invade host tissues without exhibiting a ''fibroblastic'' morpholo gy. (C) 1984 Wiley-Liss, Inc.