Metabolic pathways and energy sources for tumors
Warburg's effect is quoted many times to describe the faulty metabolic pathways in tumor cells. Tumor cells which are rapidly dividing are known to create a hypoxic microenvironment which does not support glucose oxidation. Under these circumstances, glycolysis becomes a dominant metabolic pathway to generate energy for the rapidly dividing tumor cells. However, this may not be the complete story. In recent years, there has been a tremendous amount of work being done to explore the metabolic pathways involved in various tumors. All this now depicts a newer reality where glycolysis instead of being "The pathway" is now thought to be one of the pathways used by the tumor cells. Of interest are the protein metabolic pathways such as glutamine and proline pathways, The nucleic acid metabolic pathways and my present interest, the fatty acids pathways.
If we consider that alternative pathways such as fatty acid oxidation, protein metabolic pathways, then all the proteins involved in those pathways also have to be re-characterized and should be viewed in a new light. This would in turn mean that the two way categorization that usually happens in Cancer biology as good/bad, tumor promoter/tumor suppressor etc should be discarded. Rather the context becomes more important to understand the role of a particular protein or a metabolic pathway. So for example, a signaling pathway such as LKB1/AMPK pathway could act as tumor promoter in one type of tumor while it can also act as a tumor suppressor in another type of tumor. Blind generalization then should be avoided from the authors in peer-reviewed publications and also from mainstream media. The latest example of this blind generalization came out recently. A high profile article discussed how fatty acid oxidation can enhance and enrich CD36 positive tumor cells for metastasis initiating cells. CD36 is a fatty acid receptor and is also involved in oxidation of long chain fatty acids such as palmitic acid. This work also implied that dietary lipids can enhance the metastatic potential of tumor cells. Few days later I came across a tweet "#TCGA data support new finding in mice that metastasis-initiating cells rely on dietary lipids". While this may be true in many tumor systems but not in all the systems. In fact the TCGA data from firebrowse shows downregulation of CD36 from many tumor systems. All this do suggests that scientists ought to give more attention to the context and characterize the signaling pathways according to the context.
Another great example also comes from a recent work. The authors were characterizing the metastatic spread of ovarian cancers to abdomen. They found that particularly omentum, a fat depot is the site of metastatic spread. The authors deduced that in order to survive in this niche place of excessive fat filled space, the tumors also might be using the fat as fuel. Indeed their hypothesis was correct and cells were utilizing the fatty acid oxidation as main energy source and indeed AMPK pathway is now thought to be a tumor promoter in this tumor. Therefore context-specific characterization would go a long way in moving away from generalization and thus developing newer and better therapeutic and diagnostic strategies.
If we consider that alternative pathways such as fatty acid oxidation, protein metabolic pathways, then all the proteins involved in those pathways also have to be re-characterized and should be viewed in a new light. This would in turn mean that the two way categorization that usually happens in Cancer biology as good/bad, tumor promoter/tumor suppressor etc should be discarded. Rather the context becomes more important to understand the role of a particular protein or a metabolic pathway. So for example, a signaling pathway such as LKB1/AMPK pathway could act as tumor promoter in one type of tumor while it can also act as a tumor suppressor in another type of tumor. Blind generalization then should be avoided from the authors in peer-reviewed publications and also from mainstream media. The latest example of this blind generalization came out recently. A high profile article discussed how fatty acid oxidation can enhance and enrich CD36 positive tumor cells for metastasis initiating cells. CD36 is a fatty acid receptor and is also involved in oxidation of long chain fatty acids such as palmitic acid. This work also implied that dietary lipids can enhance the metastatic potential of tumor cells. Few days later I came across a tweet "#TCGA data support new finding in mice that metastasis-initiating cells rely on dietary lipids". While this may be true in many tumor systems but not in all the systems. In fact the TCGA data from firebrowse shows downregulation of CD36 from many tumor systems. All this do suggests that scientists ought to give more attention to the context and characterize the signaling pathways according to the context.
Another great example also comes from a recent work. The authors were characterizing the metastatic spread of ovarian cancers to abdomen. They found that particularly omentum, a fat depot is the site of metastatic spread. The authors deduced that in order to survive in this niche place of excessive fat filled space, the tumors also might be using the fat as fuel. Indeed their hypothesis was correct and cells were utilizing the fatty acid oxidation as main energy source and indeed AMPK pathway is now thought to be a tumor promoter in this tumor. Therefore context-specific characterization would go a long way in moving away from generalization and thus developing newer and better therapeutic and diagnostic strategies.
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