Cell-cell clustering of fibroblasts, called nemosis, leads to a massive growth factor, proteolytic and proinflammatory response. Culturing fibroblasts in conditioned medium collected from HaCaT keratinocyte cell panel representing different stages of skin carcinogenesis had a differential effect on fibroblast nemosis. Non-malignant keratinocytes had a nemosis-inhibiting effect on fibroblasts as seen by inhibition of COX-2 protein expression. Conditioned medium from malignant cells promoted fibroblast nemosis by inducing higher levels of COX-2, HGF/SF and VEGF. Even a small amount of malignant medium converted the inhibitory effect of benign medium, whereas non-malignant medium neutralized the nemosis-promoting effect of malignant medium. In collagen co-cultures benign keratinocytes caused a nemosis-inhibiting effect on fibroblast spheroids by inhibiting COX-2 induction, while with malignant keratinocytes myofibroblastic differentiation of fibroblasts was seen.