Chronic
inflammation has long been associated with neoplastic progression. Our group had recently shown that the addition of a large number of apoptotic
tumor cells to the tumor microenvironment induces a potent acute inflammatory reaction capable of promoting
melanoma growth; however, primarily necrotizing cells do not cause such a reaction. Here, we show that potent inflammatory agents, such as
lipopolysaccharide (LPS) and
carrageenan, also promote growth of subtumorigenic doses of
melanoma cells, having no effect on
melanoma proliferation in vitro. Inhibition of
5-lipoxygenase (5-LOX) seems to have a pivotal role in this model because
caffeic acid and
MK886, a FLAP (5-LOX-activating protein) inhibitor, partially hindered
tumor growth induced by apoptotic cells or LPS. Other
enzymes of the
arachidonic acid pathway,
cyclooxygenase-1 and
cyclooxygenase-2, seem to have no participation in this
tumor promoter effect, as the inhibitor of both
enzymes (
indomethacin) did not alter
melanoma growth.
Leukotriene B4 (
LTB4), the main product of the 5-LOX pathway, was able to induce growth of subtumorigenic inocula of
melanoma cells, and a
LTB4 receptor antagonist inhibited acute
inflammation-associated
tumor growth. Addition to the
tumor inflammatory microenvironment of
eicosapentaenoic acid, an omega3-polyunsaturated
fatty acid with anti-inflammatory properties, or
leukotriene B5, an
eicosapentaenoic acid-derived
leukotriene, significantly inhibited
tumor development. These results give new insights to the mechanisms through which
inflammation may contribute to
tumor progression and suggest that LOX has an important role in
tumor progression associated with an inflammatory state in the presence of apoptosis, which may be a consideration for apoptosis-inducing treatments, such as
chemotherapy and
radiotherapy.