Multistep Nature of Metastatic Inefficiency

Abstract

In cancer metastasis, only a small percentage of cells released from a primary tumor successfully form distant lesions, but it is uncertain at which steps in the process cells are lost. Our goal was to determine what proportions of B16F1 melanoma cells injected intraportally to target mouse liver 1) survive and extravasate, 2) form micrometastases (4 to 16 cells) by day 3, 3) develop into macroscopic tumors by day 13, and 4) remain as solitary dormant cells. Using in vivo videomicroscopy, a novel cell accounting assay, and immunohistochemical markers for proliferation (Ki-67) and apoptosis (TUNEL), we found that 1) 80% of injected cells survived in the liver microcirculation and extravasated by day 3, 2) only a small subset of extravasated cells began to grow, with 1 in 40 forming micrometastases by day 3, 3) only a small subset of micrometastases continued to grow, with 1 in 100 progressing to form macroscopic tumors by day 13 (in fact, most micrometastases disappeared), and 4) 36% of injected cells remained by day 13 as solitary cancer cells, most of which were dormant (proliferation, 2%; apoptosis, 3%; in contrast to cells within macroscopic tumors: proliferation, 91%; apoptosis/necrosis, 6%). Thus, in this model, metastatic inefficiency is principally determined by two distinct aspects of cell growth after extravasation: failure of solitary cells to initiate growth and failure of early micrometastases to continue growth into macroscopic tumors.

Axis of evil: molecular mechanisms of cancer metastasis

“…Thus, all explanations of 'success' of the metastatic axis contain a strong element of determinism. Whereas the early steps in the metastastic campaign are completed very efficiently, metastasis is an inefficient process in its later steps, especially the regulation of cancer cell growth at the secondary sites (Luzzi et al, 1998;Cameron et al, 2000;Chambers et al, 2002). Given that spread of the tumor to distant organs is usually lethal, more intense studies of these molecular mechanisms assume general importance to develop more effective anticancer strategies.…”

Visualizing extravasation dynamics of metastatic tumor cells

“…Consequently, late steps of the metastatic cascade, such as tumor cell extravasation, are not fully appreciated and poorly understood. In fact, most of the data is inferred from low-resolution in vivo studies or endpoint assays that indirectly monitor tumor cell extravasation by quantifying secondary tumor formation in mouse or chick CAM models, days or weeks after tumor cell inoculation into the circulation (Luzzi et al, 1998;Podsypanina et al, 2008;Sahai, 2007;Townson and Chambers, 2006). However, given that the circulation is a hostile environment, it seems plausible that successful metastatic cells would rapidly exit the vessel within a few hours or days to gain access to ECM-rich tissues and other survival factors.…”

Development of Anti-Cancer Stem Cells as Theranostic Agents in the Treatment of Different Cancer Types: An Update

“…Very small percentage of tumor cells belong to primary tumors that can cross circulation and forms distant metastatic abrasion. Almost 90% cancer cells released from primary tumor can cross one or more of three steps of the metastatic process while only 2% are able to become micro metastatic, out of which only 0.2% are capable of inducing angiogenesis and form distant metastatic lesions [7]. Our immune system is quite efficient to recognize and destroy foreign invaders such as viruses, bacteria and abnormal or unfamiliar cells in the body with the help of white blood cells.…”