"Spontaneous" Neoplastic Transformation in Vitro: a Form of Foreign Body (Smooth Surface) Tumorigenesis

Abstract

Explants of subcutaneous connective tissue from adult BALB/c mice into plastic petri dishes were serially subcultured and tested for tumorigenicity in two ways: by the subcutaneous implantation of cells attached to plastic plates (1 by 5 by 10 millimeters), and by the subcutaneous injection of cells suspended in saline. Cells grown in vitro for 18 or more days before being implanted attached to a plastic plate (2.4 x 10(4) to 3.4 x 10(5) cells per plate) formed tumors after 24 to 79 weeks. The latent period before tumor appearance correlated inversely with the time spent by the cells in tissue culture. Cells inoculated in saline suspension (10 to 100 times the above number per plate) did not form tumors until after 84 days in vitro; plates alone did not induce tumor formation within more than 1 1/2 years of implantation. The tumors arising from the plate-attached cells were transplantable without plates and histologically appeared to be undifferentiated sarcomas. It is well established that smooth-surfaced foreign bodies, regardless of their chemical composition, will produce sarcomas when transplanted subcutaneously in rodents. We interpret our data, particularly the decrease in tumor latent period with time spent in tissue culture, as indicating that a smooth surface was acting as a carcinogen first in vitro (the surface of the tissue culture dish) and then in vivo (the surface of the plastic plate).

Beyond foreign‐body‐induced carcinogenesis: Impact of reactive oxygen species derived from inflammatory cells in tumorigenic conversion and tumor progression

“…However, this possibility was low 6 ; (iii) culture medium contained carcinogenic substances 7 ; (iv) culture dish secreted carcinogenic substances. 8 Heppner, one of their contemporary researchers, speculated that inflammation was one of the possible causative factors for foreign-body-induced tumorigenesis. 77 Since then, we have expanded the experimental systems and demonstrated that foreign-body-induced inflammation and its-derived ROS are definitely the cause for the conversion.…”

“…[4][5][6] They showed that cells of nontumorigenic but immortalized mouse cell lines or freshly isolated connective tissues from mice were converted into lethally growing tumors of monoclonal origin in mice after they were implanted, being attached to foreign bodies. 4,5,8,9 They suggested at least 5 causes for the conversion: (i) immortalized cells acquired preneoplastic phenotype for the lack of anchorage-independent growth property, and thus the substrate-attached cells grew exponentially in vitro and lethally in vivo 4,5 ; (ii) activation of endogenous oncornaviruses. However, this possibility was low 6 ; (iii) culture medium contained carcinogenic substances 7 ; (iv) culture dish secreted carcinogenic substances.…”

“…One of the epoch-making experimental studies in this aspect was established by Dr. Boone and his colleagues. [4][5][6][7][8][9] They observed tumorigenic conversion of immortalized cell lines after implantation of the cells attached to foreign bodies such as a piece of plastic plate or glass bead. Following their finding, we expanded the experiment to tumor progression, namely, the final stage of carcinogenesis acquiring malignant properties, and revealed that inflammatory-cell-derived reactive oxygen and nitrogen species were actually involved in the malignant progression.…”

Molecular Mechanisms of Inflammation-Induced Carcinogenesis

“…The malignant conversion is not restricted to mouse cells; we also observed the same phenomenon in human colonic adenoma cells [53] or in rat regressive mammary tumor cells [54]. The concept of the foreign body-induced carcinogenesis was established by Boone & Takeichi [55]. They attached immortalized but non-tumorigenic mouse fibroblast cell lines to a piece of plastic plate or glass beads and implanted them into a subcutaneous space in mice; then the fibroblast cells were converted into tumorigenic ones.…”

“…They attached immortalized but non-tumorigenic mouse fibroblast cell lines to a piece of plastic plate or glass beads and implanted them into a subcutaneous space in mice; then the fibroblast cells were converted into tumorigenic ones. First, they speculated that some carcinogenic chemical substances were diffused by the foreign body [55]. Heppner, a contemporary researcher, speculated that foreign-body-induced inflammation was one of the possible causative factors for the conversion [56].…”