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K.M. Cholewa: World Cancer Day 2015, Marijuana, and the Cannabinoid System

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It’s World Cancer Day so I’d like to tell you a few things I’ve learned from a writing project I’m working on.

The reason why marijuana (cannabis) has an effect on human bodies is because the plant-based cannabinoids in marijuana fit into the receptors of the human cannabinoid system.  The human cannabinoid system is involved in many of the body’s activities including modulation of the cell cycle which of course would have something to do with cancer.

Human cannabinoid receptors can be activated by

  • Human cannabinoids made by the body, endocannabinoids (we know of two)
  • The plant-based cannabinoids in marijuana (we know of many, but it is primarily CBD and THC that are studied for their therapeutic applications)
  • Synthetic cannabinoids such as those that may be manufactured by pharmecudical companies.

The cannabinoids would be considered “ligands” that serve as “agonists” to the cannabinoid receptors of which we know of two, CB1 and CB2. Activation of the CB1 receptor is necessary for the psychotropic effects. Activation of the CB2 receptor does not result in psychotropic effects.

Cannabinoid receptors are of a class of cell membrane receptors that fall under the G protein-coupled receptor superfamily. “G protein-coupled receptors (GPCRs) play important roles in a variety of biological and pathological processes. They are considered among the most desirable targets for drug development.” Studies have demonstrated that many GPCRs have been implicated in tumor formation and the metastasis of many human cancers. This class of receptors have been found to be involved with many diseases. They are “the target of approximately 40% of all modern medicinal drugs.1

Because the G-protein-coupled receptor known as the cannabinoid receptor is involved in the cell cycle, it has been explored by scientists as a target in the treatment of cancer.

Below are three processes undertaken by cells, healthy or cancerous, and the action of the cannabinoid receptor  in that process when cancer is present.

Apoptosis 

Cell proliferation and cell death both have a role in a correctly functioning body and the cannabinoid system is involved in keeping this cellular process functioning properly.2  In study after study of different kinds of cancer, cannabinoid therapy has been found to induce apoptosis in cancer cells – meaning it leads them to self-destruct. Yet, unlike chemotherapy, cannabinoid therapy leaves healthy cells unaffected.

These studies have been conducted in vitro (lab studies) and in vivo (primarily mouse studies). They have entailed the use of both plant-based and synthetic cannabinoids.

Angiogenesis  

Angiogenesis involves the process through which new blood vessels are formed from existing ones. This process, however, can be utilized by disease.

Angiogenesis is a fundamental step in the transition of tumors from a benign state to a malignant one. Just as healthy tissue requires oxygen and nutrients for hits growth, so do tumors. “To this purpose a tumor induces the formation of new blood vessels from vessels present in the surrounding healthy tissues. Once formed, these vessels not only facilitate the growth of the primary tumor, but also favor the spreading of cancer cells to distant organs (metastasis).” 3

Because tumor angiogenesis is critical to the growth of a tumor, blocking angiogenesis results in dramatically reduced tumor growth. This has led to the use of angiogenesis inhibitors in the treatment of cancer.4  Studies have demonstrated that exogenous cannabinoids, such as those found in cannabis or synthetic cannabinoids, can inhibit tumor angiogenesis. 5

Cell Migration

The orchestrated movement of cells to specific locations is critical to tissue formation, such as that which occurs during embryonic development and wound healing. However, cell migration is also the basis for metastasis, which is the spread of a cancer from one organ or part of the body to another not directly connected with it.

Two teams led by molecular biologists Dr. Pierre Desprez and Dr. Sean McAllister at California Pacific Medical Center in San Francisco found that the vast majority of metastatic cancer cells tended to express high levels of ID-1, a natural protein that is highly involved in the embryonic development of humans, a process which involves cell migration.6

After embryonic development, the ID-1 protein essentially turns off and stays off. But when “Desprez manipulated cells in the lab to artificially maintain a high level of ID—1 to see if he could stop the secretion of milk, he discovered that these cells began to look and act like cancer cells.” 7 8

The researchers found that though the ID-1 gene regulates the normal development and death cycle of epithelial cells in healthy people, in people with cancer “something goes haywire with the molecular mechanisms that regulate this complex system and cells encoded with the ID-1 gene begin to proliferate uncontrolled.” 9

CBD, a cannabinoid in cannabis, has been found to have a corrective impact on these ID-1 genes. The researchers found that when aggressive breast cancer cells were combined with CBD in a petri dish, “the metastasizing ID-1 cells simply turn off and return to a normal, regulated state.” 10 The authors of the study believe that CBD will have similar impacts, that is restoring cells to a regulated state, in other cancer types where high levels of ID-1 are present.

This cannabinoid found in cannabis, CBD, also has been found to be able to inhibit the migration of tumor cells, particularly of glioma cells (brain cancer cells).

Other interesting tidbits:

  • WIN-55,212-2 is a synthetic cannabinoid activating both CB1 andCB2 receptors. Sami Sarfaraz of the University of Wisconsin in 2005 conducted a study which demonstrated for the first time that expression levels of both cannabinoid receptors, CB1 and CB2, are higher in human prostate cancer cells than in normal cells. Her study determined that WIN-55,212-2 treatment with androgen-responsive cells resulted in an inhibition of cell growth. The treatment also induced apoptosis (cell death) of the cancer cells. 11
  • Many cancer cells tend to “overexpress” cannabinoid receptors. For example, a common skin cell expresses CB1 receptors. A skin cancer cell expresses not only more cannabinoid receptors, but also CB2 receptors in addition to the CB1 receptors in healthy skin cells.
  •  Liver cancer cells also exhibit an overexpression of CB1and CB2 receptors. Further, the expression of CB1 and CB2 receptors has been found to increase from cells of a normal liver to one with chronic hepatitis to one with cirrhosis. 12 In other words, as the liver deteriorates, the number of cannabinoid receptors on those cells increase. Not only that, univariate analysis, that is, an analysis considering a single variable as the unit of analysis, has indicated that disease-free survival of liver cancer is significantly better in those patients with high CB1 and CB2 expression versus those with low CB1 and CB2 expression. 13

 

We think of cancer cells as being mindless and destructive to the very organism that allows for them to exist, and this is true. Yet, it also seems that some cancer cells are generating the very mechanisms that will induce the biochemical cascade that leads to their destruction and that mechanism lies in the cannabinoid system.

In study after study it is also demonstrated that while cannabinoid therapies impact cancer cells, they do not impact healthy ones, which is very different than chemotherapy that takes down the good cells with the bad.

And just one more thing because it’s interesting:

In 2008, the University of Minnesota released a study in the May edition of Cancer Research indicating that they may have found the earliest event in sun-induced skin cancer. When the researchers went looking for the gene that played a role in the absorption of UV radiation, they started with the assumption that because plants interacted with UV light for the purposes of photosynthesis, the human gene that interacts with UV light may be similar in structure. “When they compared plant genes for UV receptors to human genetic material, they found that the human genes for cannabinoid receptors matched.” When researchers genetically modified mice and removed their cannabinoid receptors, the mice were resistant to the “development of UV-induced inflammation and skin tumors.” In addition, researchers found that when cannabinoid receptors were exposed to UV light, they “changed from an inactive to an active state, indicating they had absorbed and responded to the light.”

Researchers didn’t know why cannabinoid receptors respond to both UV light and cannabinoids

That’s the news in recognition of World Cancer Day 2015. More from this project as it progresses. For more information, contact me here.

 

K.M Cholewa

This post originally appeared on K.M. Cholewa’s blog yesterday. K.M. is the author of Shaking Out the Dead.

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