Contractor Replenishment Cell

CRC right? Lord I don’t miss that place. Truly the embodiment of “hurry up and wait” because even the most waiting-est branch of service, Marine Corps, got ahead of us in line. Wait in Texas to wait in Kuwait to wait in another desert. Seems legit. What was this about about? Oh. CRC as in colorectal cancer. Even worse than the previous CRC. 

In 70-80% of cases, CRC arises from adenomatous polyps in the colon. Who would have guessed thats where they would start? These polyps come about when the normal cells of the epithelium gain a genetic mutation in the Wnt signaling pathway. Normally the Wnt keeps the cells proliferating to maintain the lining of the colon, which is good. When Wnt is turbocharged you get overgrowth, which is bad. Too much of a good thing eh? I forget if I have said this in other posts, if only there was a way I could go back and read them, but the more a cell divides the more chances for a mutation to occur that would transform it into cancer. So the Wnt makes the cells divide more rapidly, leading to more mutations and then you get the polyps first, then CRC. The division itself does not create the mutations, but genetics or environmental factors damage DNA making the cells more susceptible to the changes. 

Non-modifiable risk factors include older age (though cases are getting younger), personal or family history of colon cancer, genetic diseases such as Lynch Syndrome, African American, and inflammatory bowel disease. I suppose you could modify prior history of radiation treatment for other cancers and work to keep IBD under control but either way, they are risks. Modifiable risks include low fiber & high fat diet, excessive processed meat, sedentary lifestyle, diabetes, obesity, smoking, and excessive or chronic alcohol consumption. Other risks have been proposed such as heart diseases (might be the shared risk factors), cystic fibrosis, acromegaly, immunosuppression, cholecystectomy, infection with S. bovis, H. pylori, HPV, F. nucleatum,  and JC virus. 

For S. bovis there is good research showing that the bug is associated with CRC in that between 25-70% of those with S. bovis bacteremia also have CRC. These harbinger bugs are interesting. But does the S. bovis cause the cancer or cancer cause an overgrowth of the bacteria? Beats me. Cancer, and the underlying risks, along with generally tough treatments seem like they would do a number on one's microbiome. Antibiotics for more infections or for prophylaxis do damage to the native flora balance. Perhaps the unhealthy diet aspect of CRC risk leads to a more inviting environment for the bug? 

On the other side of the coin, there are ways to reduce the risk of CRC. Primarily, address the modifiable risk factors listed above. For fiber, for every 10g increase in daily fiber it is estimated that the risk of CRC drops ~10%. Even if fiber doesn't prevent cancer, it is worth it to prevent constipation, I hate constipation with a passion. Does anyone love constipation? I hope not. So after that digression, aside from fiber, intake of calcium, vitamins D and B6, folate, and aspirin have been shown to modestly affect the risk of CRC. Oh and of course, statins and garlic help as well. Don't they help everything? 

That was a lot of characters for talking about how mutations can occur. But I enjoy yapping so deal with it. As these changes occur, the cells move from normal to hyperplasia and/or dysplasia. Hyperplasia is the overgrowth of cells and can be seen with the enlargement of glandular cells in pregnancy or increase in muscle size from weight training. That being said, hyperplasia can be normal, but think about if the cells effected were to grow large enough to block the colon? Or compress important vessels? Yeah, not good and why even benign tumors can become a hazard depending on their growth. 

Dysplasia refers to the abnormal growth of cells leading to further changes and mutations. An example is a dysplastic nevus. A normal collection of melanocytes, a nevi, that starts to change and the cells begin to look different. Key to this, they still appear similar to the original nevi, when they completely change this is anaplasia or metaplasia. Another example is MDS where immature blood cells never mature. Kinda like me, I grow older but am still a 15 year old boy. Anyways, these are often pre-cancerous conditions, needing just a bit more of a push to reach cancer status.  

Metaplasia is the change in cell type from one to another. Examples of this are squamous epithelium to columnar epithelium in Barrett's esophagus and glandular to squamous epithelium from the cervix to the vagina. The latter is normal, caused by pH changes and the former considered pre-malignant, caused by smoking. Anaplasia is the "backward formation" of cells from their mature stage to ambiguous looking cells of all shapes and sizes. Pleomorphisms for you smarty pants out there. They may have more cytoplasm or bigger nuclei or several nuclei. Generally, all the cells of a certain type should look similar, so this is bad. The cells may also assume structures unrelated to the surrounding cells. Anaplasia does not normally pertain to CRC but when it occurs, it is usually more aggressive than other subtypes. 

The above mentioned dysplasia can occur 10-15 years before becoming malignant, and why removal is key. This early treatment is important, to quote Lotfollahzadeh et al., "The most important prognostic indicator is the pathological stage at presentation supported by data from the SEER observed overall survival (OS) at 5-years rates for colon in stage I includes 74%; stage IIA, 66%; stage IIB, 58%; stage IIC, 37%; stage IIIA, 73%; stage IIIB, 46%; stage IIIC, 28%; and stage IV, 5%." With that in mind, the National Cancer Institute puts 20-22% of all CRC diagnosed with distant metastases (stage IV) and 35% with regional spread (stage IIIA-IIIC). All that to say globally more than 700,000 people a year die from CRC and between 1.2-1.9 million new cases a year. 

Again  referring to ancient history, that is a past blog I think, I mentioned that CRC incidence has been decreasing however the incidence in those under 50 has increased. These earlier-onset CRCs are more likely to be later staged as well. Many of the risk factors previously discussed apply to any age group, but may be coming more common as the way of life changes in America and around the world. We are more sedentary than ever, "desk" jobs abound and keep us bound to chairs. Processed food? We have so many different choices I can never decide what junk filled snack I want to eat and default to pancaked. As my dad tells me not infrequently, when he was younger they had one brand of soda and two of chips in the gas station. Environmental factors may be a bigger issue now. Look at the news about "forever chemicals" or microplastics or various other newer, now common place compounds. I didn't see anything definitively but the National Cancer Institute thinks it may play a role. Don't forget obesity! Do I need to add that we are all getting fatter? Could it be 5G? The microwaves from our cellphones? The alien probes the stick where the sun don't shine? I don't know but I have tin foil underwear to match my hat. 

This is getting long but we haven't even gotten to the fun parts yet. Fun you say? No, it's never fun but maybe more interesting or satisfying to talk about. Patience grasshopper. Most people who decide to get checked via colonoscopy, flex sigmoidoscopy, PILLCAM, or other option do so for suspicious symptoms; rectal bleeding, anemia, abdominal pain. Routine screening or incidental findings account for about 20% of CRC and lower stage at diagnosis. There are several blood and stool tests that test for different tumor markers as well, with varying degrees of efficacy, colonoscopy is still the gold standard. 

Once the CRC has been found if at all possible, resection is the key. This can be done via endoscopy with good results and low recurrence for smaller, local, non-invasive cancers confined to the colon. Risks are low with a 0.8% mortality rate. Surgical resection is too complicated for me to understand right now, let's just say they cut it out along with 12 lymph nodes. For stage II the 5 year survival is 50-65% and for stage III the same is 20-50%. Adjuvant chemotherapy usually includes fluorouracil, oxaliplatin, capecitabine, bevacizumab, and/or panitumumab to name just a few. This is given to reduce the size of tumors, eliminate undetected mets, and/or kill off the tumor cells to make it easier (hopefully) to cut out the tumor and that when cut hopefully the tumor does not seed the surrounding areas. 

Something else interesting I read in my Google expedition was about the use of clarithromycin (CAM) to treat CRC and possibly other cancers. I talked about how itraconazole is antiangiogenic and may have a role to play in cancer treatments, CAM works differently. CAM inhibits autophagy, which confused me at first, since that is a defensive mechanism that healthy cells use to get rid of early malignant cells. Later on in cancer's life however, autophagy is used to survive stressors and lack of nutrients. In a very complicated article I won't pretend to understand, autophagy is shown to increase the ability of cancer to metastasize and become drug resistant. Don't ask me how, check out Mowers et al., in the references. Simply put, normal cells autophagy is good, cancer cells autophagy is bad. 

Ok back to present treatments. If the CRC has spread the treatment moves towards preserving quality of life. Surgery and radiation to shrink the tumor, chemo or immunotherapy for the same and to prevent spread. For CRC that has spread throughout the peritoneal cavity, peritoneal carcinomatosis, hyperthermic intraperitoneal chemotherapy is sometimes used. This is where chemo drugs are heated up and pumped into the peritoneum for a short time and circulated out, kinda like dialysis. Not everyone agrees it is a smart treatment choice, but interesting to consider and may be more effective in advanced peritoneal carcinomatosis. 

I would love to keep going but at 2000ish words you're sick of me by now. At least you know a little bit more about CRC, maybe more than you cared to know, but tough luck. This post was a long time coming as I have been MIA for a while, weddings take a lot of time, but sorry to disappoint you, I'm back. Let's see how long I can keep it up. Love. y'all 

A) Serrated adenocarcinoma; B) Mutinous carcinoma: C) Signet ring carcinoma: D) Medullary carcinoma

References 

ACS, CDC, NIH, NCI, and WHO statistics on CRC from their respective websites.

Autophagy in cancer metastasis by Mowers et al., in Oncogene 2017

Basic Pathology (8th ed.) by Kumar et al., 2007

Colorectal cancer statistics, 2023 by Siegel et al., in CA Cancer J Clin 2023

Colorectal cancer: Epidemiology, risk factors, and protective factors from UpToDate by Macrae et al., updated 2023 

Image of 4 different histology of CRC from Remo et al., in Cancers 2019

Mayo Clinic and Memorial Sloan Kettering Cancer Center CRC pages.

Repurposing Drugs in Oncology (ReDO)-clarithromycin as an anti-cancer agent by Van Nuffel et al., in Ecancermedicalscience 2015

Significant Rise of Colorectal Cancer Incidence in Younger Adults and Strong Determinants: 30 Years Longitudinal Differences between under and over 50s by Sifaki-Pistolla et al., in Cancers 2022

Streptococcus gallolyticus Bacteremia and Colorectal Carcinoma from Gastroenterology 2019 by Wong, Ho, & Lee

The association of Streptococcus bovis/gallolyticus with colorectal tumors: the nature and underlying mechanisms of its etiological role by Abdulamir et al., in the Journal of Experimental & Clinical Cancer Research 2011

What's Driving the Rise of Colon Cancer in Young Adults? from ASCO DAILY NEWS by Karippot and Parikh in 2023

Yale Medicine Colorectal Cancer: What Millennials and Gen Zen Need to Known by Katella in 2023