Wednesday, September 21, 2011

Understanding Cancer Metastasis 1

A cancer cell is a pale cast of  thought, pregnant with desire,  packed with motive and reasoning  more murderous then all ill-intent!

It was a cool dark night. Not a chirp from a bird or a howl from an owl. The trees were still. The flowers limp with dew. Not a soul inhabited the streets, save one dark shadow. The face masked and with gloves to cover all skin only the windows to his cloaked soul shone through. He weaved in and around the trees after stepping out of his bungalow; lurking behind the walls of other homes, seeking opportunity and stealth. He let out  a soft bird-call that was answered immediately from beyond and another shadowy figure  emerged and as quickly disappeared into the thicket of darkness. The game was afoot.

The object of their desire was the wealth in one lone house perched amidst the weeping willows and the might oaks. That house was silent. The dog lay sleeping in its little abode guarding only its midnight dreams. One of the robber crossed the street and with speed and an artful craft making nary a sound, he jumped the fence with ease, crossed over and threw a half-eaten steak in front of the dog that barely stirred, to rob him off his scent. He then proceeded carefully, using the dexterity of his fingers and the learned manipulation of a simple right-angled tool and opened the multi-pronged door lock. A hiss sounded and then a low tone. The place was alarmed. The other robber appeared from beyond the shadows and moved to the opposing wall panel that housed the brains of the alarm system and using a cell phone and two wires hijacked the system into quiet obedience. Again with light-footed efficiency and agility one walked straight to the library, unhinged the gold-framed photo of the owner and behind it exposed the safe – the heart of the owner’s life-long enterprise. The safe was no match to his ingenuity. It opened without a squeal or clamor. The other robber surreptitiously and without so much as a sound gathered other valuables. A life was undone.

Imagine the cloaked robbers as cancer cells. It is the same sociopathic behavior of ingratiation without lack of empathy for the host and a constant self-perpetuating desire. That same motivation feeds both. It is how cancer spread (metastasizes) occurs. Surprised? You shouldn’t be. Let us take a short journey into the fledgling field of metastasis.

The cancer cell, like the masked, cloaked robber uses similar stealth and tact to circumvent the host defense, for there are many hurdles that favor the normal organs against the spread of disease and all have to be neutralized one by one. [Italics represent quotes from various studies listed below in references]

Spread: A. Primary tumor, B. Local invasion E, Lymphatics D. Blood vessel, F. Fascia

First Hurdle: The cancer cell has to grow and multiply. For this, it co-opts the vascular system (blood supply) and releases hormones in its environs. It also, through communications within the normal surrounding community of cells via cross-talk, establishes a quid-pro-quo relationships in the form of, “I am here, you are here, lets be friends” kind of way. 
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Soon having established the groundwork for attaining the nutrients for itself to grow, it manipulates its neighbors into transitioning from their normal functioning selves into cells that unknowingly and inadvertently help in the choreographed dance of stealth and duplicity. There is a close relationship between the metabolic needs of the cancer cells and that of the host micro environment. Not only do the metabolic needs of the cancer cell but those of the host human plays a significant role in perpetuation and progression of this disastrous of all maladies, they also enhance or suppress it:
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Genetic alterations that are associated with cancer often occur in these same signaling pathways, which suggests that both environmental and genetic factors influence the metabolic heterogeneity that is present across tumors… Indeed clinical studies have linked altered whole-body metabolism to cancer development, progression and poor treatment outcomes. Indeed, obesity, hyperglycemia and insulin resistance are all associated with an increased risk of developing cancer and are associated with worse clinical outcomes in patients with cancer… Increased circulating levels of insulin and insulin-like growth factor (IGF) have been linked with cancer progression, which suggests that obesity and insulin resistance promote cancer at least in part by activating signaling pathways that drive cell growth. These same signaling pathways also drive nutrient uptake into cells and regulate enzymes in glycolysis, which implies that hormonal changes can have important indirect effects of cancer. Furthermore, elevated levels of glucose alone may promote increased glucose uptake in some cells, and lower circulating levels of glucose are associated with better cancer treatment outcomes

The well known Warburg effect after Otto Heinrich Warburg, who hypothesized that the cancer cell needs two pathways for survival: the glycolytic pathway whereby the cell breaks down the glucose to obtain energy and the Lactic Acid pathway, whereby the cancer cell needs to eliminate the excess byproduct of glucose consumption (waste product), is alive and well. Targeting both sides and not affecting the normal cell is a challenge that consumes many in the field of oncology.

In the same context, Insulin Growth Factors (IGFs) are shown to increase tumor proliferation by activating the phosphoinositide 3-kinase (P13-K) pathway. This pathway is affected by the nutrient availability and the pathway signaling inhibition by drugs downstream can be impeded by the excess of nutrients, thus the signal once impeded by such an overabundance of resource, may not reach the target inside the nucleus to initiate growth. An agent that seems to influence the m-TOR, a downstream path, of the P13-K pathway is a drug called, Rapamycin. However in the presence of excess nutrients, such as, glucose the efficacy of Rapamycin is compromised. It is thus important for the human host not to indulge in food and therefore obesity. Excess food and thus obesity are confounding factors that help the robbers rob!

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