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Relationships between Chemotaxis, Chemotactic Modulators, and Cyclic Nucleotide Levels in Tumor Cells¹

Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0W3

Like many freely moving cells, Walker 256 carcinosarcoma cells respond to chemotactic stimuli. Since cyclic nucleotides are involved in the chemotaxis of other cells, we have examined the action of several nucleosides and nucleotides as chemoattractants and as modulators of tumor cell movement. We have also studied the effect of chemoattractants and prostaglandins on intracellular cyclic nucleotide levels and the effect of prostaglandins as modulators of chemotaxis. Of the agents studied, only the cyclic nucleotides and prostaglandins were found to modulate cellular motility. Neither cyclic adenosine 3':5'-monophosphate (cAMP) nor cyclic guanosine 3':5'-monophosphate (cGMP) was a chemoattractant, but cGMP and N⁶,O^2'-dibutyryl cyclic guanosine 3':5'-monophosphate at low concentrations (10^-10 M to 10^-8 M) enhanced chemotaxis by 80 ± 15%, and both cAMP and N⁶,O^2'-dibutyryl cyclic adenosine 3':5'-monophosphate had an inhibitory effect at concentrations >10^-6 M. Chemotaxis was suppressed by 21 to 100% in media depleted of Ca²⁺ and/or Mg²⁺, but in the presence of 10^-8 M cGMP, there was partial recovery of the chemotactic response. In response to chemotactic stimulation, there was a 28 to 60% rise in intracellular cAMP within 30 sec. This returned to basal levels within 2 min. Intracellular cGMP levels became elevated 3- to 3.5-fold after this time. Incubation of cells with prostaglandins A₁ and F₂ stimulated chemotaxis at lower concentrations (10^-7 and 10^-9 M, respectively) and resulted in elevation of cGMP, while incubation with prostaglandin E₂ resulted in inhibition of chemotaxis and a rise in cAMP levels.

¹ This work was supported by a grant from the National Cancer Institute of Canada.

² To whom requests for reprints should be addressed.

³ Clinical Research Associate of the National Cancer Institute of Canada.

Received 4/29/82. Accepted 1/26/83.