Autophagy: Energy Independence?
We were surprised to find that experimental hybrids and metastatic melanoma cells expressing high levels of β1,6-branched oligosaccharides also seemed to be in a state of autophagy.
Autophagy is “self eating” wherein a cell’s cytoplasmic components are engulfed and digested as a temporary energy source in times of nutrient deprivation, for example under hypoxic conditions in the absence of a blood supply. While autophagy is associated with cancer cell death pathways, paradoxically it is also a predictor of worse patient outcome in a variety of cancers.
We proposed that, should autophagy be linked to phagocytosis in cancer cells as it is in macrophages, nutrients could be continuously phagocytosed from external sources (cellular debris, matrix fragments, etc.) and digested in autophagolysosomes. Perhaps such a system would ensure a positive metabolic energy balance during migration from avascular areas to more vascularized ones or during tumor neo-angiogenesis.
New Targets for Therapy
Thus, while much more work needs to be done to establish whether the fusion theory is operative in human cancer, circumstantial evidence is growing for the widespread involvement of fusion in tumor progression.
In my opinion, a stepwise mutation model cannot readily explain acquisition of the complex gene-expression patterns necessary for migration and metastasis. Not only does the fusion theory explain the onset of metastasis through a single initiating event but actual data from macrophages-melanoma hybrids reveal that fusion causes just what the theory predicts it should.
Looking ahead, this could open up many new potential targets for therapy, for example, development of therapies for suppression of cancer cell fusion or for targeting GnT-V, β1,6-branched oligosaccharides and autophagy. But, we need to learn more before such ideas can be translated to the clinic. I would urge more academic scientists and biotechology companies to consider entering this most interesting area of cancer research.