Joy Wang

Background: Colorectal cancer is currently the third most common cancer type, while also representing the second most lethal. Sequential accumulation of genetic and epigenetic abnormalities are involved in the transformation of healthy colorectal epithelium toward neoplasms and metastasis¹. Sporadic onset of CRC comprises the majority of cases (70%), from factors such as diet, lifestyle, alcohol and tobacco use. The chromosomal instability pathway plays a role in the onset of colorectal tumors, and is characterized by loss of heterozygosity of the long arm of Chromosome 18 and chromosomal abnormality³. It is characterized by the activation of certain oncogenes (KRAS & BRAF) and inactivation of tumor suppressor genes (APC and TP53)². Lithium chloride is already in clinical use, which stimulates CTNNB1 by inhibiting GSK3. Additionally, NSAIDs and celecoxib block CTNNB1-dependent transcription in CRC³. The most widely used chemotherapy agents are derived from 5-fluorouracil, capecitabine (5-FU prodrug), irinotecan, and oxaliplatin. These are DNA damaging agents that affect all rapidly dividing cells, and are therefore toxic and should be used in a short therapeutic window¹. New therapies are targeting specific genes that are thought to be involved in the progression of colorectal traditional serrated adenomas, with some studies looking at the role of SMOC-1 proteins, which regulate BMP signaling involved in regulation of cell growth, differentiation, and apoptosis in multiple tissues.

Objective: In this narrative review, we explored the mechanisms by which SMOC gene influences progression of colorectal serrated adenomas and its role in BMP signaling.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2023 using the following keywords: “colorectal cancer”, ” serrated adenoma”, ” genetic mechanisms of CRC”, ” SMOC”, “CRC therapeutics”, and “chromosomal instability pathway”.

Results: SMOC proteins compete with BMP ligands for binding to HSPGs, allowing BMP ligands to spread, and can act as both expanders and antagonists of BMP signaling.⁴ SMOC-1 functions negatively in LON-2/glypican manner and positively in a DBL-1/BMP manner to regulate BMP signaling⁴. Lon-2/glypican is a conserved negative regulator of BMP signaling, so increased BMP signaling resulted from mutations targeting SMOC-1 interaction with Lon-2 glypican. BMP ligand (DBL-1) binds full length SMOC-1 in vitro to regulate BMP signaling. SMOC proteins are also able to bind mature BMP dimers, further regulating BMP signaling pathways. The loss of BMPR1A signaling fibroblasts resulted in substantial histological changes, where the villi appeared to be longer and wider, with numerous polyps that could be observed throughout the small intestine. In the colon, substantial hyperproliferation was seen and the crypt length was increased 3.6-fold. BMP7v may present a therapeutic antiangiogenic and prodifferentiation effect, sensitizing cancer stem cells to standard and targeted therapies.⁷ BMP7v was given in vitro with standard chemotherapy to human colorectal cancer stem cells, and rendered these cells sensitive to oxa plus 5-FU in vitro treatment regardless of mutational profile, the same chemotherapeutic that was completely ineffective in vivo, with colony-forming ability also notably compromised⁷. 20–30% of colorectal cancer is thought to develop through the serrated pathway, which is related to increased MAPK/ERK pathway activity and BRAF mutations⁵.

Conclusions: Studies have found that SMOC-1 protein functions in a negative and positive manner to regulate BMP signaling involved in progression of colorectal traditional serrated adenomas. Loss of BMPR1A in fibroblasts increases MAPK-ERK signaling, which is associated with the serrated pathway of CRC development. BMP7v is a possible candidate for treatment of colorectal tumors.

Works Cited:

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2. Bach DH, Zhang W, Sood AK. Chromosomal Instability in Tumor Initiation and Development. Cancer Res. 2019;79(16):3995-4002. doi:10.1158/0008-5472.CAN-18-3235
3. Wielandt AM, Hurtado C, Moreno C M, et al. Characterization of Chilean patients with sporadic colorectal cancer according to the three main carcinogenic pathways: Microsatellite instability, CpG island methylator phenotype and Chromosomal instability. Tumour Biol. 2020;42(7):1010428320938492. doi:10.1177/1010428320938492
4. DeGroot MS, Williams B, Chang TY, et al. SMOC-1 interacts with both BMP and glypican to regulate BMP signaling in C. elegans. PLoS Biol. 2023;21(8):e3002272. Published 2023 Aug 17. doi:10.1371/journal.pbio.3002272
5. Ouahoud S, Westendorp BF, Voorneveld PW, et al. Loss of bone morphogenetic protein signaling in fibroblasts results in CXCL12-driven serrated polyp development. J Gastroenterol. 2023;58(1):25-43. doi:10.1007/s00535-022-01928-x
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