Figure 1.

Schematic representation of multi-site cancer formation by multigenesis and how to distinguish multigenesis from metastasis. Germ (G), stem (S), progenitor (P) and terminal (T) cells are represented by solid, crossed, slashed and hollow circles, respectively. Subsequent to a mutation that changes a normal cell (without slash across the circle) into a cancer cell (with a slash across the circle), depending on the nature of cancer-initiating cells (CICs), the clones (encircled by a dashed polygon) may contain different compositions of cells at different differentiation stages. There is also some intrinsic cell age heterogeneity in all clones which is indicated in one way by showing the generation succession with solid arrow lines. The continued existence of the mother cell over the different development stages is indicated by dashed arrow lines as shown for germline cells. A mutation in a germ cell may pass into offspring if it occurs at any pre-senescent stage. The distinction between a cancer cell translocated from a primary tumor site (site A) to a secondary site (site B) and a cancer cell originated from an indigenous cell in the same site (site B) may be made by determining a difference in mutations and/or in cell age even if the cells are otherwise genetically identical. Alternatively, an artificial marker may be introduced into offspring cells of the CICs during their reproduction in a primary cancer site so that these cells are distinct (indicated by a thick slash across the circle) from the rest. This experimental approach may offer a way to distinguish metastatic cancer cells from indigenous cancer cells even if they share the same mutations due to a convergence in the mechanisms of carcinogenesis. The growth of tumors at the different sites may be influenced by the environmental conditions at the different sites so that differential tumor growth rates can be seen even for the same CICs. In addition, metastatic cancer cells may have different fates at the different "soils"; some may establish and proliferate while some may die (as indicated by double heavy slashes). These complexities of multi-site cancers are selectively represented in the diagrams, too.