Does it make sense to target one tumor cell chemotactic factor or its receptor when several chemotactic axes are involved in metastasis of the same cancer?

Abstract

The major problem with cancer progression and anti-cancer therapy is the inherent ability of cancer cells to migrate and establish distant metastases. This ability to metastasize correlates with the presence in a growing tumor of cells with a more malignant phenotype, which express certain cancer stem cell markers. The propensity of malignant cells to migrate and their resistance to radio-chemotherapy somewhat mimics the properties of normal developmentally early stem cells that migrate during organogenesis in the developing embryo. In the past, several factors, including cell migration-promoting cytokines, chemokines, growth factors, bioactive lipids, extracellular nucleotides, and even H(+) ions, were found to influence the metastasis of cancer cells. This plethora of pro-migratory factors demonstrates the existence of significant redundancy in the chemoattractants for cancer cells. In spite of this obvious fact, significant research effort has been dedicated to demonstrating the crucial involvement of particular pro-metastatic factor-receptor axes and the development of new drugs targeting one receptor or one chemoattractant. Based on our own experience working with a model of metastatic rhabdomyosarcoma as well as the work of others, in this review we conclude that targeting a single receptor-ligand pro-metastatic axis will not effectively prevent metastasis and that we should seek other more effective therapeutic options.

Keywords: C1P; Cancer metastasis; HGF; Pro-metastatic microenvironment; S1P; SDF-1.

Fig. 1

The difference between chemotaxis and chemokinesis. Cells may respond to a pro-migratory factor in two different ways: by directed movement, in the process chemotaxis, or by random multidirectional movement, in the process of chemokinesis. Both mechanisms may be involved in egress of cancer cells from the primary tumor

Fig. 2

In vitro Transwell migration assay. Cells to be tested are placed in the upper chamber, and the migration-promoting factor to be tested for chemotaxis is placed in the lower chamber. If the factor is to be tested for chemokinesis, it is added at the same time to both upper and lower chambers. Cells that migrate to the lower chamber are counted and compared with cells that had migrated in medium without the pro-migratory factor (the control Transwell inserts)

Fig. 3

In vivo seeding efficiency assay for human cells. Human cells exposed ex vivo (primed) to a pro-metastatic factor or a receptor blocking agent are subsequently injected i.v. into immunodeficient mice. Mice can be additionally irradiated with 360 cGy. The number of human cells can be detected in murine organs by FACS (after labelling cells with fluorochrome or transducing with GFP) or by detecting the level of human DNA in murine organs