Silence is Golden, Noise is Cancer

Silence is Golden, Noise is Cancer

"LISTEN to me, " said the Demon as he placed his hand upon my head. " The region of which I speak is a dreary region in Libya, by the borders of the river Zaire. And there is no quiet there, nor silence." (From Silence-A Fable by Edgar Allan Poe)

The cell cycle provides a powerful metaphor of silence and speech. In the Go phase of interphase, cells are not dividing but are inactive. They are silent, voiceless, and unspeaking. In the G1, S, and G2 phases, the cells are actively dividing. They are noisy, uproarious, and full of brouhaha, hubbub, boom, kapow and other onomatopoeic descriptors. Ushered in from the Go phase by the checkpoint guards, the cells march ahead to breed, replicating with abandon in the S maternity. They are then discharged to the G2 phase where they are inspected by more checkpoint guards before being let into the M phase for mitotic division. The whole process is an orderly, choreographed, and well-rehearsed process, sort of like a timeless military drill.

The checkpoint guards are the enforcers of this process. The P53 and Ataxia-telangiectasia mutated (ATM) genes are some of the meanest, no-nonsense guards deployed to ensure that this process remains flawless. Many others have tough names: DDC, RAD9, MEC3, RAD24, RAD17. They wield formidable weapons that can deter even the most hardened elements from passing through. Heck, they can trigger mechanisms that cause violators to become suicidal and blow themselves up (funny that they call this apoptosis). Once in a while though, the checkpoint guards can be corrupted to let in undesired elements like damaged DNA. When this happens, cancer happens. And there is no quiet here, nor silence as cells are actively dividing.

But cancer happens also when a category of inactive, reticent, and quiet cells are compelled to become noisy, to move through the noisy phases of the cell cycle. Here' s how it happens. Quiescence is largely reversible, sort of like issuing and withdrawing gag orders on a person. It is important as it allows cells to self-renew, protects them from myelotoxic offenses, facilitates the maintenance of the stem cell compartment, helps cells to avoid mutations which occur with frequent cycling, facilitates the replenishment of injured cycling populations, and reduces oxidative stress. However, some cells are inclined to introversion but when pinched they can howl loudly, very loudly, and make all sort of disconcerting noises. Such is the nature of cancer stem cells (CSCs) which are quiet stem cells turned noisy.

The origin of cancer stem cells has not yet been fully determined and the exact mechanisms through which stem cells are formed are unknown. Currently, there are 3 theories that seek to explain the CSCs origin. The first theory states that they arise from stem cells, the second from progenitor cells, and the third from differentiated cells. The hypothesis that suggests CSCs arise from stem cells supposes that self-renewing stem cells are subjected to a mutation event which results in defects in the cell cycle regulation thereby generating CSCs. Mutation of progenitor cells or activation of self-renewal genes in normal progenitor cells is blamed for the rise of CSCs in the progenitor cell hypothesis. According to this theory, CSCs are very much like stem cells and have the ability to form other specialized cells or to self-renew. The differentiated cell theory avers that de-differentiation of differentiated cells together with stimulation of self-renewal genes can yield CSCs. De-differentiation of the cells can occur through the genetic reprogramming by specific stem cell factors and this makes them to become pluripotent. The CSCs expand in an unregulated manner and differentiate arbitrarily resulting in differentiated tumor cells. Studies have linked quiescent CSCs to cancers of the pancreas, brain, blood, breast, and colon and CSCs have been isolated from melanomas, and pancreatic, breast, and ovarian tumors.

However, the role of CSCs in solid tumor has not yet been fully proven. Quiescent cancer stem cells are able to tolerate hypoxic conditions and can also withstand conditions of acidic pH as well as nutritional paucities. These are often the prevailing conditions in a tumor and the ability of the cancer stem cells to withstand these conditions is perhaps the most critical factor ensuring their survival. These quiescent cells can become active, divide actively and form secondary tumors through mechanisms that are yet undiscovered. Therefore, quiescence and cancer are highly dependent on the capacity of the cells to endure variable, out-of-cycle conditions.

A large percentage of drugs used in the treatment of cancer target cycling cells and leave quiescent CSCs untargeted. This is cited as one of the main contributors to resistance against cancer chemotherapy as these CSCs remain alive to cause the relapse and advancement of disease. It's time we slapped the quiescent cells with gag orders and told them to shut up; time we left this dreary region in Libya, by the borders of the river Zaire where there is no silence. Time we designed novel anticancer drugs targeting quiescence.

The granulocyte colony-stimulating factor (G-CSF), Wnt inhibitors, interferon, histone deacetylase inhibitors, and CXC motif receptor-4 antagonists typify the efforts at designing drugs targeting quiescence in adult stem cells. GCSF is widely used in the clinical management of neutropenia, mobilization of HSCs in the circulation, and in enhancement of the sensitivity of leukemic cells to cytotoxic drugs. Wnt inhibitors such as reservatrol, quercetin, curcumin, and ICG001 are also being mentioned as probable anti-cancer agents since Wnt signaling helps to maintain plays quiescence in cancer stem cells. Interferons, in particular IFN-? and IFN-? transiently and actively activate the proliferation of HSCs in vivo and this is being exploited in the treatment of cancer. Histone deacetylase inhibitors (HDACi) can cause non-proliferating cells to become apoptotic as well as alter the expression of genes associated with the survival, self-renewal, and niche interactions of cancer stem cells such as leukemic stem cells.

It has been shown that leukemia stem cells resistant to imatinib only become apoptotic when exposed to a combination of HDACi and imatinib. The binding of CXCL12 to the CXC motif receptor-4 antagonists (CXCR4) leads to the localization of cancer stem cells to their niche. Agents whose actions antagonize this binding can therefore serve as effective anticancer agents targeted against cancer stem cells. For instance, AMD3100 is used to prevent the localization of leukemia stem cells in their niche by preventing the binding of CXCL12 to the CXCR4 receptor in a selective and reversible manner. It also causes the quick mobilization of cancer stem cells and is used in combination with GCSF. AMD3100 also stops the interaction between the bone marrow stroma and the acute myeloid leukemia (AML) blasts and this assists in making the blasts become more sensitive to anticancer drugs besides enhancing their mobilization to the peripheral blood. This agent is however still under investigation. A very attractive approach involves targeting the regulatory signals involved in stem cell quiescence. Some of the intrinsic mechanisms involved in stem cell quiescence and which are attractive targets include p53 signaling, reactive oxygen species (ROS) such as ATM and FoxOs, hypoxia inducible factor-1?, nuclear factor of activated T cellsc1, and negative regulators of mTOR such as PML, PTEN, and Fbw7. Extrinsic mechanisms for regulating stem cell quiescence include angiopoietin-1 (Tie2), thrombopoietin, osteopontin,Wnt/B-catenin signaling, N-cadherin and integrins, and TGF-beta and proteins associated with morphogenesis of the bone.

Most of the drugs targeting quiescence are still at the developmental stages and require further enhancement and optimization before their efficacy can be proven. For instance, studies show that even though GCSF is variously associated with improved outcomes for chronic myeloid leukemia (CML) patients following co-administration with imatinib, some studies do not find any improvements when these 2 drugs are used in the treatment of CML. Further, not many studies have been conducted to determine the usefulness of this approach.

But there is still hope. Hope that silence will finally prevail.

"Then I grew angry and cursed, with the curse of silence, the river, and the lilies, and the wind, and the forest, and the heaven, and the thunder, and the sighs of the water-lilies. And they became accursed, and were still. And the moon ceased to totter up its pathway to heaven --and the thunder died away --and the lightning did not flash --and the clouds hung motionless --and the waters sunk to their level and remained --and the trees ceased to rock --and the water-lilies sighed no more --and the murmur was heard no longer from among them, nor any shadow of sound throughout the vast illimitable desert. And I looked upon the characters of the rock, and they were changed; --and the characters were SILENCE."

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