Friday, May 18, 2012

The Resilience of Melanoma

In class we’ve learned that one of the hallmarks of cancer is resisting cell death. A cancer cell’s resistance to apoptosis and its manipulation of the cell cycle are essentially what make it a cancer cell. In an article titled Apoptosis and Melanoma Chemoresistance, by Maria Soengas and Scott Lowe from the University of Michigan, the specific type of cancer – melanoma, an aggressive skin cancer – is discussed, and its notorious reputation for being resistant to many current chemotherapy mechanisms. Scientists have identified molecules involved with apoptosis, and their alteration in melanoma, and say these are providing new insights into the molecular basis for melanoma chemoresistance. They are now out to develop new strategies to counter these effects and improve in their battle against the disease.

One of the great mysteries of melanoma is that the tumor cells seem to acquire the capability to avoid the immune system regulations in place and avoid the cytotoxic action of different cytotoxic mechanisms – for example, DNA damage (like methylation, which we discussed in class, or crosslinking), microtubule destabilization, or topoisomerase inhibition, as the article states. It’s also mentioned that chemotherapy doesn’t help a large portion of patients, therefore concluding that drug resistance is likely not a primary consequence of acquired genetic changes selected during therapy but instead is inherent to the malignant behavior of melanoma cells. The scientists state that the aggressive behavior of melanoma cells stems from their intrinsic survival features of their paternal melanocytes fed by additional changes acquired during tumor progression.

Regarding drugs like etoposide, scientists have argued that tumor cells may avoid DNA damage by downregulating topoisomerase II, the target of the drug. It’s been found to be downregulated or mutated in melanoma cells, more specifically, even if its levels may not correlate with drug sensitivity. It’s also possible that a hyperactivation of DNA repair mechanisms occurs in the presence of a cancer drug. Since drugs do activate DNA damage sensors in melanoma cells, this indicates that melanoma cells do sense the drugs but have developed alternatives to prevent or counteract their action. “Apoptosis” was the term used to describe the consequences of chemotherapeutic drugs – for example, intense membrane blebbing, chromatin condensation, and nuclear fragmentation. This is being used in new drugs which aim somehow to affect the proteins which control apoptosis in the cell for multiple tumor types. However, as I mentioned, resisting apoptosis is one of the hallmarks of cancer, so inducing it is very complicated.

Figure 1
It was learned that tumor suppressors, like p53 which we discussed, engage apoptotic pathways to prevent the aggregation of cancer cells. These pathways are activated as a result of DNA damage, from carcinogens for example. The main apoptotic inducers are a series of cysteine-aspartyl-proteases, called caspases, which act in cascades leading to apoptosis. There are many stimuli which affect apoptosis, but there are two main categories, as we see in Figure 1. The intrinsic pathway is linked to mitochondrial functions and the extrinsic pathway is linked to membrane-linked “death receptors.” One can see the many regulation points of intrinsic and extrinsic apoptosis. Intrinsic relies on cytochrome c, released from the mitochondria and binds to Apaf-1, an apoptotic activator. This creates an apoptosome which binds to caspase 9 and engages in a series of events which eventually lead to the death of the cell. The extrinsic pathway is initiated by the binding of cytokines (TNF-α, TRAIL, FasL) to receptors in the plasma membrane. The receptor becomes activated and eventually binds to other proteins which are linked to inactive profroms of procaspase 8; this is called a death-inducing signaling complex.

Mutations in the p53 pathway are shown to be linked to chemoresistance. What’s strange however is that melanomas display a low frequency of p53 mutations, even though they’re known for being resilient. This could be possible because p53 doesn’t in fact influence treatment responses in these tumors, or the abnormal phosphorylation of p53 by Chk2 kinase.

Figure 2
Three different pathways help to encourage the normal apoptosis of cells: PI3K/AKT/PTEN, NF-kB, and Raf/MAPK. These pathways are summarized in Figure 2 as well. The PI3K (phosphoinositide 3-kinase) pathway is mainly involved in response to multiple mitogens. It targets many things like cell proliferation, migration, and survival. AKT can activate NF-kB, and is regulated by PTEN. PTEN counteracts survival signals and promotes apoptosis. PTEN has been shown to reverse the invasive phenotype of melanoma cells as well, making it a good target for drugs. In short, NF-kB is involved in many things, and has functions in angiogenesis, the cell cycle, differentiation, migration, and survival. It monitors the expression of survival factors which interfere with mitochondrial and death receptor-mediated apoptosis. Regarding the last pathway, mutations here can result in the disengagement of cell cycle controls, metastasis, and the blocking of proapoptotic stimuli. B-Raf, involved with Ras, when mutated may inhibit apoptosis downstream of cytochrome c release, also making it a target for drug therapy.

Melanoma, for reasons not yet known, is more resistant to chemotherapy than other cancers. This could simply be because of a more efficient program for cell death and survival pathways. They suppress critical tumor control mechanisms in both their own cells and other stromal cells. These cells have overcome the consequences of their abnormal hyperproliferation. Mediators of oncogenic activation have been shown to increase the levels of Apaf-1 as well. The reprogramming of cell-cell adhesion molecules in transformed cells may inactivate things like PTEN, and affect other pathways, so that the cell invades uncontrollably and resists apoptosis. The cells also resist outside forces like when traveling in blood vessels and evading the immune system.


Although, unfortunately, this article does not have a specific solution in mind when it comes to treating melanoma, I think that it offers an informative discussion about the control of apoptosis. I think it’s important for doctors and scientists alike to understand the pathways involved in cellular survival and death so that developments can be made both in melanoma treatment and cancer therapy as a whole. Hopefully the cellular mechanisms discussed in this article will lead to improvements in drug therapies for melanoma. I think, from what I read in the article, one of the most promising targets seems to be the NF-kB pathway. Because the pathway is involved in so many essential cell functions (as mentioned in class, it has pleiotropic effects), from regulation of the cell cycle to apoptosis, it would be such an accomplishment to develop a drug which targets even part(s) of this pathway. I think that by targeting something like the IAPs or TRAF (see Figure 2), it would essentially “inhibit the inhibition,” creating two negatives, which would ideally drive extrinsic apoptosis. I know scientists are working to target specific molecules like these to treat melanoma, and relate them to other cancers. How would one design a drug that would only target the pathways in the cancer cells, leaving the healthy surrounding stromal cells untouched? Mentioned at the end of the article is an anticancer proteasome inhibitor PS-341, which as been reported to act selectively on a series of tumor cells without affecting normal counterparts. This, as a coincidence, is associated with the NF-kB pathway! The specificity of this molecule should be studied in order to gain a better understanding of how we can target only certain pathways of certain cells in a cancer patient.