Tumor cell dissemination: emerging biological insights from animal models and cancer patients

Abstract

Circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) are increasingly recognized for their potential utility in disease monitoring and therapeutic targeting. The clinical application of CTC/DTC requires better understanding of the biological mechanisms behind tumor dissemination, the survival of DTCs, and their activation to aggressive growth from dormancy. Recent research using animal models of DTCs and CTCs have provided novel insights into these processes. Here, we discuss these findings in the context of results obtained from the clinical analyses of CTCs and DTCs, which demonstrate that the animal models mimic, in many aspects, the complex situation in patients.

Figure 1. Schematic representation of the steps in the dissemination, survival and expansion of metastatic tumor cells

Under the influence of stromal cells in the primary tumor microenvironment, tumor cells undergo EMT or use other means of invasion to escape from the primary tumor (Friedl and Alexander, 2011). Platelets protect CTCs in circulation and further stimulate EMT by TGFβ and NFκB signaling. Tumor-derived factors and exosomes mobilize bone marrow derived cells to form pre-metastatic niche to promote the seeding and expansion of metastasis. Stromal component at the metastasis niches enhance tumor survival, stemness and immune evasion. CTCs derived from the primary tumor or metastasis may engage in multi-directional seeding to the primary tumor or other metastasis sites. Examples of genes mediating different steps of tumor dissemination are listed in Table 1.