Lymphatic or hematogenous dissemination: how does a metastatic tumor cell decide?

Abstract

The formation of distant metastases is the deadliest phase of cancer progression. Although numerous studies have identified genes and mechanisms that affect metastasis after tumors have reached secondary sites, our knowledge about how cancer cells initially gain access to systemic circulation is limited. Since tumors can enter the blood directly by intravasating into venous capillaries or indirectly via lymphatics, it is important to evaluate the relative contributions of both pathways as routes of egress from the primary site. Insights into tumor and stromal factors governing the intravasation process may help explain why certain tumors exhibit "preferred" pathways for metastatic dissemination, both clinically and in experimental animal models.

Figure 1

Tumors possess blood vessels (red) and, in some cases, lymphatics (green). Experimental ablation of intratumoral lymphatics does not inhibit lymph node metastasis (top). Eliminating or inhibiting the activation of peritumoral lymphatics has been shown to reduce lymphatic spread (bottom).,, In addition, intratumoral lymphatics are absent in many tumors that nevertheless metastasize to lymph nodes. These observations imply that peritumoral lymphatics mediate the majority of tumor cell dissemination. (Flt4-Ig, soluble Flt4 receptor/VEGFR3; adeno, adenoviral delivery).

Figure 2

After surgical orthotopic implantation of human prostate PC-3 cells into nude mice, associations were observed among lymph node metastasis, circulating tumor cells and lung micrometastases. Left, significant numbers of circulating tumor cells in the blood were detected only in mice that bore macrometastases in both the lumbar and renal lymph nodes. Middle, similarly, most lung metastases were seen in mice with both lymph node sites invaded. Right, lung metastases were correlated with the presence of circulating tumor cells in the blood. (Reproduced with permission from ref. 30).

Figure 3

Two possible pathways for metastasis could explain why, in a mouse model of prostate cancer, hematogenous spread is observed only in the presence of significant lymphatic spread. (1) The tumors might be incapable of intravasating directly into blood vessels, so metastatic cells enter venous circulation indirectly via lymphatics (“metachronous seeding”). Or, the tumor is completely nonmetastatic until mobilized to metastasize via both lymphatic and hematogenous routes at the same time (2).