The Multifaceted Role of Heme in Cancer

Abstract

Heme, an iron-containing porphyrin, is of vital importance for cells due to its involvement in several biological processes, including oxygen transport, energy production and drug metabolism. Besides these vital functions, heme also bears toxic properties and, therefore, the amount of heme inside the cells must be tightly regulated. Similarly, heme intake from dietary sources is strictly controlled to meet body requirements. The multifaceted nature of heme renders it a best candidate molecule exploited/controlled by tumor cells in order to modulate their energetic metabolism, to interact with the microenvironment and to sustain proliferation and survival. The present review summarizes the literature on heme and cancer, emphasizing the importance to consider heme as a prominent player in different aspects of tumor onset and progression.

Keywords: cancer; heme; iron; metabolism; microenvironment (ME).

Figure 1

Molecular mechanisms of dietary heme induced colorectal carcinogenesis. Heme in red/processed meat alters multiple molecular and genetic mechanisms in the colonic epithelium resulting in colorectal carcinogenesis. Heme accumulation induces the formation of the CHF that leads to cytotoxic damage to surface epithelial cells. Moreover, heme causes peroxidation of lipids and NOC formation resulting in free radical formation and genetic mutations. Labile iron, resulting from heme degradation, induces the formation of ROS that lead to oxidative damage and genetic mutations. Finally, heme alters the intestinal flora enhancing the heme-induced cytotoxic effects.

Figure 2

Putative processes controlled by increased heme synthesis in cancer. The reason why tumors enhance heme synthesis is unknown. Several hypotheses have been explored: increased heme synthesis could control energy production, ADP/ATP exchange between mitochondria and cytosol, TCA cycle cataplerosis, P53 activity and stability, as well as the activity of hemoproteins and of heme binding proteins involved in the circadian clock machinery.

Figure 3

Impact of heme on tumor microenvironment. Other than sustaining cancer cells growth (1), heme could also potentially affect other processes within the microenvironment, including macrophage polarization (2), the angiogenic potential of tumor endothelial cells (3), matrix remodeling by cancer-associated fibroblasts (4), and nerve-cancer cross-talk (5).

Figure 4

Potential effects of heme-based therapies. The multifaceted role of heme in cancer suggests the possibility to develop novel therapies targeting heme metabolism. The picture highlights the potential beneficial effects of heme-based therapies on cancer cells as well as tumor microenvironment.