Rimonabant And Colorectal Cancer

Targeted killing of neoplastic colon cells; abstract:

Colorectal cancer (CRC), like other tumor types, is a highly heterogeneous disease. Within the tumor bulk, intra-tumoral heterogeneity is also ascribable to Cancer Stem Cells (CSCs) subpopulation, characterized by high chemoresistance and the unique ability to retain tumorigenic potential, thus associated to tumor recurrence. High dynamic plasticity of CSCs, makes the development of winning therapeutic strategies even more complex to completely eradicate tumor fuel. Rimonabant, originally synthesized as antagonist/inverse agonist of Cannabinoid Receptor 1, is able to inactivate Wnt signaling, both in vitro and in vivo, in CRC models, through inhibition of p300-histone acetyltransferase activity. Since Wnt/β-Catenin pathway is the main player underlying CSCs dynamic, this finding candidates Rimonabant as potential modulator of cancer stemness, in CRC. In this work, using established 3D cultures of primary colon CSCs, taking into account the tumor heterogeneity through monitoring of Wnt activity, we demonstrated that Rimonabant was able to reduces both tumor differentiated cells and colon CSCs proliferation and to control their survival in long term cultures. Interestingly, in ex vivo model of wild type human organoids, retaining both architecture and heterogeneity of original tissue, Rimonabant showed no toxicity against cells from healthy colon epithelium, suggesting its potential selectivity toward cancer cells. Overall, results from this work provided new insights on anti-tumor efficacy of Rimonabant, strongly suggesting that it could be a novel lead compound for CRC treatment.

Yet More On The Microbiota Colon Cancer Connection

A review paper asserts, from the abstract:

From the abstract:

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering from colorectal cancer is about 4%-5% and the risk for developing CRC is associated with personal features or habits such as age, chronic disease history and lifestyle. In this context, the gut microbiota has a relevant role, and dysbiosis situations can induce colonic carcinogenesis through a chronic inflammation mechanism. Some of the bacteria responsible for this multiphase process include Fusobacterium spp, Bacteroides fragilis and enteropathogenic Escherichia coli.

It is becoming increasingly clear that modification of gut microbiota, possibly through diet and/or probiotics, will become an important tool in the prevention and treatment of many diseases, including CRC.

Diet And Colorectal Cancer: Nucleus To Cell Membrane

Review article:

The International Agency for Research on Cancer recently released an assessment classifying red and processed meat as "carcinogenic to humans" on the basis of the positive association between increased consumption and risk for colorectal cancer. Diet, however, can also decrease the risk for colorectal cancer and be used as a chemopreventive strategy. Bioactive dietary molecules, such as n-3 polyunsaturated fatty acids, curcumin, and fermentable fiber, have been proposed to exert chemoprotective effects, and their molecular mechanisms have been the focus of research in the dietary/chemoprevention field. Using these bioactives as examples, this review surveys the proposed mechanisms by which they exert their effects, from the nucleus to the cellular membrane. In addition, we discuss emerging technologies involving the culturing of colonic organoids to study the physiological effects of dietary bioactives. Finally, we address future challenges to the field regarding the identification of additional molecular mechanisms and other bioactive dietary molecules that can be utilized in our fight to reduce the incidence of colorectal cancer.

Certain bioactive dietary factors have a protective effect against colorectal cancer, and scientists are investigating the cellular mechanisms behind these effects.

Eat your fiber!

Millennials with colorectal cancer

Fifteen percent of all colorectal cancer patients are diagnosed before age of 50. This percent will continue to grow, as the incidence of this type of cancer increases among people under the age of 50. According to this article, the fastest increase in incidence is observed in the cohort of 20- to 39-year olds.

The mentioned article discusses the  increasing incidence rates, but does not mention the possible causes for the worrisome trend.

I read some of the 200+ comments under the news. My conclusion is that our population is somewhat confused about the true reasons of why colorectal cancer is killing more and more young people.

Some of the readers mention genetics (heredity), but I assure you that humans cannot change their DNA so fast as to account for the present statistics.

Some mention GMOs, preservatives, and chemicals. I doubt the contribution of these as well. We need more evidence and proven mechanism of the agents.

Some blame the trend on our diet. I would say – a close guess. Our diet, our eating and physical activity habits leading to obesity are the true reason. Seventy percent of the U.S. adult population is overweight/obese. 

How does obesity cause cancer? Obesity creates an environment rich in adipokines, diverse molecules that can stimulate several signaling pathways. Such pathways could allow the survival and uncontrolled proliferation of already mutated cells. This adipokine - induced stimulation eventually allows for an earlier onset of not only colorectal cancer, but also other types of cancer.

Today in addition to colorectal cancer, the people younger than 50 have a higher risk of being diagnosed with thyroid cancer, cancer of the uterus, pancreatic cancer, kidney cancer, leukemia, and stomach cancer (data are from SEER database of NCI/NIH available online). 

Among the younger than 50, colorectal cancer and cancer of the uterus exhibit increased mortality (in addition of the increased incidence rate).

All of the mentioned types of cancer could be associated with obesity.

It is as simple as that: obesity kills us in many ways. It is disheartening that not too many have the courage to state this clearly. Instead, the prevalent idea is that we need to do more research to establish the reasons for the cancer incidence trend. 

Instead of more research, spend the money on teaching the kids what to eat and how/when to eat it. This will be a true prevention approach with enormous impact not only on the cancer incidence among the young, but also on all other chronic diseases that kill us.

CANCERS OF THE YOUNG

You must have heard that cancer incidence and mortality in the U.S. are decreasing, right?  For most types of cancer this is the case. However, there are a few types of cancer that are increasing in incidence, mortality, or both.

I found the data from the Surveillance, Epidemiology and End Results (SEER) database (a registry of cancer cases kept by the National Cancer Institute) informative. You can access the "search SEER" tool through this website, and if you are interested, you can obtain the breakdown of the data by gender and race.

I was interested in analyzing the data by age since there are reports that the younger U.S. population (< 50) has increased rates of incidence of colorectal cancer (I have previously discussed this). Therefore, I focused on the pattern of cancer incidence and mortality among different age groups. 

The SEER data confirmed that there is a distinct pattern of increased incidence and mortality of specific cancers.  For example, only for people younger than 50, the mortality from colorectal cancer has been increasing for the indicated five-year period; whereas, the mortality from uterine (endometrial) cancer has been increasing for all ages (see Table I). 

Cancer Site	Average Annual Percent Change in Mortality, 2009-2013
	Ages <50	Ages 50+	Ages 65+	All ages
Thyroid	0.5 (-0.2, 1.2)	0.8# (0.6, 1.0)	1.0# (0.7, 1.2)	0.8# (0.6, 1.0)
Brain & ONS	0.8 (-1.7, 3.3)	0.4 (0.0, 0.9)	0.6 (0.0, 1.3)	0.5 (-0.1, 1.1)
Colon & Rectum	1.3# (0.8, 1.8)	--	--	--
Uterus	1.5# (1.2, 1.9)	1.9# (1.1, 2.6)	1.1# (0.6, 1.6)	2.4# (1.6, 3.1)
Bladder	--	0.1# (0.0, 0.3)	0.2# (0.1, 0.4)	0.1 (0.0, 0.2)
Pancreas	--	0.3# (0.3, 0.4)	0.4# (0.3, 0.5)	0.3# (0.2, 0.4)
Liver & Bile Duct	--	3.4# (3.0, 3.7)	2.6# (2.3, 3.0)	3.0# (2.7, 3.4)
Melanoma of the Skin	--	--	1.2# (1.1, 1.4)	--
Oral Cavity/Pharynx	--	--	--	0.4 (-0.9, 1.7)

TABLE I.

95% confidence interval shown in parentheses

# - The annual percent change is significantly different from zero (p<0.05).

Stable (no increase): when the 95% confidence interval of annual percent change includes 0.

Rising (increase): when the 95% confidence interval of annual percent change is above 0.

The cancer incidence data (Table II) is even more intriguing. There are total of seven types of cancer that exhibit a trend of increasing incidence in younger adults (<50); albeit, only two types of these cancers have truly “increased” incidence according to statisticians (i.e., thyroid and kidney cancer).

Is there a unifying theme? It seems that most of the cancers that exhibit a trend of increase in incidence, mortality, or both, are associated with obesity. Since 70% of the adult US population and 30% of our children are now overweight/obese, the trends of increasing liver, pancreatic, kidney, colorectal, thyroid, uterine, and stomach cancers are probably going to be confirmed as statistically significant in another decade or so.

Cancer Site	Average Annual Percent Change in Incidence, 2009-2013
	Ages <50	Ages 50+	Ages 65+	All ages
Thyroid	2.7# (1.4, 3.9)	1.4# (1.0, 1.9)	1.1# (0.6, 1.7)	2.1# (1.5, 2.7)
Colon & Rectum	0.8 (-0.1, 1.7)	--	--	--
Uterus	0.3 (-0.1, 0.7)	0.6# (0.3, 1.5)	0.8# (0.5, 1.2)	0.6# (0.3, 0.9)
Pancreas	1.3 (-0.1, 2.7)	0.4# (-0.5, 0.4)	0.2  (0.3, 0.5)	0.5 (-0.4, 1.4)
Liver & Bile Duct	--	2.5# (1.5, 3.6)	2.3# (1.3, 3.2)	2.0# (0.9, 3.1)
Melanoma of the Skin	--	1.8# (0.6, 3.0)	2.5# (1.1, 3.9)	0.7 (-0.4, 1.9)
Oral Cavity/Pharynx	--	0.9# (0.1, 1.6)	0.9 (-0.1, 1.9)	0.5 (-0.2, 1.2)
Breast	--	--	0.1 (-1.0, 1.2)	--
Leukemia	0.1 (-1.2, 1.4)	--	--	--
Stomach	0.7 (-2.6, 4.1)	--	--	--
Kidney&Renal Pelvis	1.2# (0.3, 2.2)	--	--	--

Table II.

95% confidence interval shown in parentheses

# - The annual percent change is significantly different from zero (p<0.05).

Stable (no increase): when the 95% confidence interval of annual percent change includes 0.

Rising (increase0: when the 95% confidence interval of annual percent change is above 0.

There are also a few enigmas in these data. Note that the incidence of brain cancers is not increasing; however, there seems to be a trend of increased mortality (not according to the confidence interval, though) . One possible explanation is that the proportion of deadly brain cancers (e.g., glioblastomas) is increasing, but the total number of brain cancers does not change in a statistically significant manner. We should follow on whether the mortality of brain cancer will increase in a statistically significant manner in the next years. Gliomas, by the way, are also associated with obesity.

Another puzzling observation is that thyroid cancer incidence and mortality are both increasing (these data are statistically significant). There has been lots of noise in the media about this observation. The most prevalent explanation is that the current detection methods for thyroid cancer have become extremely sensitive, and most of the “increased” thyroid cancer burden is in fact due to the detection of very small lesions. According to the clinicians, such lesions may never develop into deadly cancers.  Well, if this is the case, why is the mortality of thyroid cancer increasing too? Is it possible that the patients with the less advanced lesions are over-treated and in fact, they die from the treatment, rather than from the neoplasm?

Questions, questions. There are too many of questions; however, no one has had the guts to address the fact that all of the cancer types on the rise are associated with increased body weight.