Thursday, September 22, 2011

Understanding Cancer Metastasis 2

This is a continuation of an explanation of cancer metastasis.

We include here a video, rather lengthy, explaining some of the latest research on cancer metastasis for your perusal.  The real explanation begins at 13 minute mark.  If you cannot see the embedded video, here is the link:

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In a recently discovered entity dubbed the Epithelial-Mesenchymal-Transition or EMT, the E to M phase transition can also go from M to E  (MET) and indicates the fluid flow of cells morphing by desire and motivation, by acquiring properties of others that have better abilities to migrate, invade and spread.  All of these phase transitions within the cancer environment occur for the sole purpose of mitigating any difficulties for escaping the firewalls erected by the basement membranes and other fascia as defenses  within the host.
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Some cancers like the alveolar cell carcinoma of the lung and the clear cell carcinoma of the ovary have a field day in “spreading” due to their proximity to an “open-field.” Both types of cancers also manipulate various cytokines and enzymes and by promoting such, they are able to modify the epigenetic system to abrogate the tumor-suppression algorithms within the DNA code from coming on board. The Phase transition, EMT is an aberrant activation of a latent embryonic Program encoded within the cells. This very deterministic behavior lends to self-renewal capability, antigenic expression and later, resistance to therapy and is the object of recent scrutiny.
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It is increasingly acknowledged that aberrant activation of a latent embryonic program - known as the epithelial-mesenchymal transition (EMT) - can endow cancer cells with the migratory and invasive capabilities associated with metastatic competence [1-3]. Moreover, several lines of evidence have converged in recent years to support the notion that not all cancer cells within a given tumor are equal in terms of their tumor-initiating potential. The emerging paradigm posits that tumor progression is driven by a small subpopulation of cancer cells - termed cancer stem cells (CSCs) or tumor-initiating cells - that exhibit two defining characteristics: the ability to self-renew and the ability to regenerate the phenotypic heterogeneity of the parental tumor [4]. CSCs have thus been implicated both in initiating and sustaining primary tumor growth and in driving the seeding and establishment of metastases at distal sites… During normal embryonic development, EMT serves to loosen cell-cell contacts and to enhance intrinsic cell motility, thus paving the way for the extensive cell movements required for gastrulation and organogenesis… EMT can be induced by a plethora of extracellular stimuli, including hepatocyte growth factor, epidermal growth factor, platelet-derived growth factor, Wnt, Notch, Sonic hedgehog and transforming growth factor beta (TGFβ) as well as components of the extracellular matrix such as collagen and hyaluronic acid and adverse conditions such as hypoxia [1,3]. These diverse stimuli trigger a multitude of signal transduction pathways that converge on several EMT-inducing TFs, including Snail, Slug, Zeb1, Zeb2, Twist, FoxC2 and Goosecoid, many of which are frequently over-expressed in breast cancers.

The breast, it may be reminded, is an organ worthy of considerable study because it undergoes expansion and then involution for each pregnancy cycle and thereby provides us with an indirect indication of the presence of breast stem cells that undergo morphogenetic branching via many transcriptional factors during these single or multiple pregnant phases. Additionally, a family of Metastatic Tumor Antigens (MTA1-3) proteins that are also involved in the spread of breast cancer:

The metastasis tumor antigen (MTA) family of proteins, MTA1, MTA2, and MTA3, are components of chromatin remodeling pathways with potential roles in breast cancer.

Using the genetic profiles of breast cancers, six different subtype populations of differing molecular signatures have been identified; luminal A, luminal B, HER2+, basal-like and  claude-like. Most chemotherapy drugs attack the cancer cells but do not address the de-novo or phase transitioned cancer stem cells that have evolved. An anti diabetic drug “Metformin” seems to address that directly by killing Cancer Stem Cells (CSCs). Now, that might be a direction towards cure should further studies confirm this violate action as being a true representative of going after the “culprit!” Imagine destroying the menagerie of propagating cancer cells with chemotherapy, targeted biologic therapy and then going after the sociopath itself!

Thus based on the predicate, which stipulates that the primary tumor is governed by different sets of molecular rules from those of the metastatic cancer elucidates the realm of differential therapy with multiple “medical” and “surgical” scalpels. Better yet, if one can choke off the system completely without affecting the normal cells remains the holy-grail! Refining the sociopath and changing his or her motivation is a daunting path since it is difficult to determine who is who. It is a difficult task indeed. But understanding the needs and depriving the aggressor may be the simplest preventative measure towards success. We might just have to live by “Dunkin Broccoli rather than Donuts.”
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Got you out of the comfort zone, didn’t I? Sorry. Let us walk a little slower. Smell the fresh air and take a deep breath once again. The entire orchestral symphony played by the cancer cell is a strategy for self-renewal and thus self-perpetuation. The cancer cell wants to survive and propagate. That is the code writ in its code. It thus manipulates its environs to suit its own needs. Just like the unmasked, and uncloaked man is a perceived normal functioning member of his household and of the larger community, yet lurking within him is the unseen evil betrayal. No one is aware, or even concerned that this mild-mannered sociopath is a burglar, aiding and abetting others to join his league.

Acquiring these traits of using enzymes to cut through the jungle of basement membranes, fatty tissue, fascia and a dense arborized collection of capillaries and supporting cellular network, is like the prince hacking at the forest in search for Snow White, only this is not the prince but the witch using her unlimited powers to dissolve and destroy so she can govern and control the purity. The cancer cell makes its escape by recruiting host micro environment features, such as the Tumor Associated Macrophages or (TAMs) to help make the break through the jungle. TAMs have the ability to secrete various dissolving enzymes to clear the path for the progress of the cancer cell and confuse its own immunity police. Macrophages thus become the unwitting accomplices in the robbery.

We will continue with this series in our nest installment.

Parvez Dara, MD FACP
Twitter: JediPD


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Anonymous said...

Happy New Year!
Health, luck and love!