Metastasis: cancer cell’s escape from oxidative stress

Monday, 01/08/2011  |   Others  |  no comments

According to a “canonical” view, reactive oxygen species (ROS) positively contribute, in different ways, to carcinogenesis and to malignant progression of tumor cells: they drive genomic damage and genetic instability, transduce, as signaling intermediates, mitogenic and survival inputs by growth factor receptors and adhesion molecules, promote cell motility and shape the tumor microenvironment by inducing inflammation/repair and angiogenesis. Chemopreventive and tumor-inhibitory effects of endogenous, diet-derived or supplemented antioxidants largely support this notion.

Metastasis has been traditionally interpreted, in a darwinistic perspective, as a process whereby genetic instability in the primary tumor fuels cell heterogeneity, allowing few metastatic clones to eventually emerge and be positively selected to disseminate cancer at distance. It has also been suggested, based on genetic disparity between primary and metastatic tumors, that metastases may arise from cells leaving the primary tumor lesion at an early stage of its local progression, and thus develop in a parallel rather than sequential fashion with respect to the lesion of origin (Klein, 2009). Either way, it is becoming increasingly clear that only a minority of malignant cells undertakes the metastatic route, and, of those, an even smaller fraction succeeds in this task. Evidence also exists that these cells may share some properties with somatic or embryonic stem cells (Barnhart & Simon, 2007; Mani et al, 2008), which has led to the hypothesis that metastases are initiated by cell clones endowed of unique self-renewal and tumor propagating capacity, i.e., by cancer stem cells (CSC).

While molecular strategies employed by metastatic cells to leave the primary tumor, intravasate, disseminate at distance and grow into new colonies are being intensively and successfully investigated, less clear is what actually prompts some tumor cells to leave the primary tumor, or, in other words, what kind of environmental pressure operates on cells bound to a metastatic fate. We know, however, that a tumor can be a very hostile environment, due to shortage of oxygen and nutrients, inflammation and immune system attacks, and that both hypoxia and inflammation promote metastasis Bertout et al, 2008; Mantovani, 2009). Thus, metastasis may ultimately represent an escape strategy from cell death.

Fig. 1: ROS and/or RNS play important and multiple roles in each of the six hallmarks of cancers. Based on the model by Hanahan and Weinberg (2000), cellular and molecular mechanism for which a role for ROS/RNS has been demonstrated are indicated for each hallmark,
in the same color.
1. GROWTH EVEN IN THE ABSENCE OF NORMAL “GO” SIGNALS: Most normal cells wait for an external message before dividing. Conversely, cancer cells often counterfeit their individual proliferative messages.
2. GROWTH DESPITE “STOP” COMMANDS: As the tumor enlarges, it squeezes adjacent tissues and therefore receive messages that would normally stop cell division. Malignant cells ignore these commands.
3. ABILITY TO INVADE TISSUES AND SPREAD TO OTHER ORGANS: Cancers usually lead to death only after they overcome their confines to the particular organ in which they arose. Cancer cells need to escape the primary tumor, invade matrix of different organs,
find a suitable metastatic niche and then grow in this secondary site.
4. EFFECTIVE IMMORTALITY: Healthy cells can divide no more than 70 times, but malignant cells need more than 70 cycles to make tumors. Hence, tumors need to enforce the reproductive limit of cells.
5. ABILITY TO STIMULATE BLOOD VESSEL DE-NOVO ASSEMBLY: Tumors need oxygen and nutrients to survive and secrete factors recruiting new branches that run throughout the growing mass.
6. EVASION FROM ENDOGENOUS AUTODESTRUCT MECHANISMS: In healthy cells, several conditions (including genetic damage or lack of ECM adhesion) activates a suicide program, but tumor cells bypass these mechanisms, thereby surviving to death messages

Oxidative Damage
However, emerging lines of evidence indicates that tumor cells also need to defend themselves from oxidative damage in order to survive and successfully spread at distance. This “heresy” has recently received important impulse from studies on the role of antioxidant capacity in cancer stem cells self renewal and resistance to therapy; additionally, the transforming activity of some oncogenes has been unexpectedly linked to their capacity to maintain elevated intracellular levels of reduced glutathione (GSH), the principal redox buffer. These studies underline the importance of cellular antioxidant capacity in metastasis, as the result of a complex
cell program involving enhanced motility and a profound change in energy metabolism. The glycolytic switch (Warburg effect) observed in malignant tissues is triggered by mitochondrial oxidative damage and/or activation of redox sensitive transcription factors, and results in an increase of cell resistance to oxidants. On the other hand, cytoskeleton rearrangement underlying cell motile and tumor-aggressive behavior use ROS as intermediates and are therefore facilitated by oxidative stress. Along this line of speculation, we suggest that metastasis represents an integrated strategy for cancer cells to avoid oxidative damage and escape excess ROS in the primary tumor site, explaning why redox signaling pathways are often up-regulated in malignancy and metastasis.

Figure 2:
Antioxidant function of redox signaling and metastasis. Unfavorable environmental conditions that favor metastasis (inflammation, hypoxia, nutrient starvation, etc.) are associated with heavy oxidative stress.We speculate that redox cascades that lead to glycolytic switch, cell proliferation and motility/invasion and are activated in metastasis have originally evolved for the purpose of rescuing normal cells fromoxidative damage and allowing tissue repair (left side of the figure). Redox switches may have subsequently been incorporated into ligand (growth factors, ECM, semaphorins)-dependent cascaded that use NOXes, and other oxidases, as components of “normal” cell signaling (right side).
Oncogene-driven carcinogenesis hijacks these cascades, leading eventually to metastasis as the malignant counterpart of the original antioxidant response (right side). Metastasis may therefore be part of an integrated strategy whereby malignant cells escape oxidative damage at the primary tumour site.

Redox Signaling
Knowledge on the molecular mechanism and the biological contexts whereby oxidants (oxygen and nitrogen species) operate as signaling molecules has been expanding at an impressive rate over the last few years (Janssen-Heininger et al, 2008). “Redox signaling” has rapidly turned into a major area of “mainstream” cellular and molecular biology, with huge implications for human diseases. Yet, why cells use to regulate basic functions like proliferation/death, motility, and energy metabolism such dangerous compounds as nitrogen and oxygen species, is still far from clear, and it is reasonable to think that safer messenger molecules and molecular devices could serve the same scope.
One attractive possibility is that redox signaling has evolved for the main purpose of allowing cells to sense and avoiding oxidative stress and damage (Figure 2). At a single cell level, this idea is consistent with the observation that oxygen and nitrogen species play a central role in cell dynamic and in the triggering of antioxidant responses, two different and complementary strategies to reduce exposure to harmful oxidants. Yet cells die if stress is too massive, or if glucose in not available to maintain redox buffers. In a multicellular organism, redox signals gain two additional important functions related to tissue repair: regulation of cell.
Source:
Pani, G., Galeotti, T., & Chiarugi, P. Metastasis: cancer cell’s escape from oxidative stress. Cancer Metastasis Rev (2010) 29:351–378. DOI 10.1007/s10555-010-9225-4
References:
Barnhart, B. C., & Simon, M. C. (2007). Metastasis and stem cell pathways. Cancer and Metastasis Reviews, 26, 261–271.
Bertout, J. A., Patel, S. A.,& Simon, M. C. (2008). The impact of O2 availability on human cancer. Nature Reviews Cancer, 8, 967–975.
Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100, 57–70.
Janssen-Heininger, Y. M., Mossman, B. T., Heintz, N. H., Forman, H. J., Kalyanaraman, B., Finkel, T., et al. (2008). Redox-based regulation of signal transduction: principles, pitfalls, and promises. Free Radical Biology and Medicine, 45, 1–17.
Klein, C. A. (2009). Parallel progression of primary tumours and metastases. Nature Reviews Cancer, 9, 302–312.
Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., et al. (2008). The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell, 133, 704–715.
Mantovani, A. (2009). Cancer: inflaming metastasis. Nature, 457, 36–37.

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