Molecular and Biological Aspects of Self-Expandable Metallic Stent Placement in Malignant Colorectal Obstruction

This article refers to:

Short-Term Outcomes of Self-Expandable Metallic Stent versus Decompression Tube for Malignant Colorectal Obstruction: A Meta-Analysis of Clinical Data

Acute intestinal obstruction is one of the major complications of malignant colorectal tumors. Approximately in 7–30% of cases, especially if tumor is located at or distal to the splenic flexure, colonic obstruction is the first symptom that draws attention to the tumorous process. In these cases, conventional emergency surgical decompression is mandatory. However, patients treated with emergency surgery have higher perioperative mortality and complications rates, higher stoma rates with more secondary stoma-reversal surgeries, and higher health costs. An alternative to surgery is endoluminal decompression. Self-expandable metallic stent (SEMS) or decompression tube (DT) techniques can be a bridging solution between urgent and elective surgical interventions. Lots of studies have demonstrated their excellent short-term outcomes; nevertheless, comparative studies between SEMS and DT have rarely been reported, and they have only a low sample number. Considering this fact, the latest meta-analysis hopefully facilitates surgeons’ decision regarding their selection between SEMS and DT. Based on the results, patients receiving SEMS benefit from higher clinical success rates, higher laparoscopic surgery rates, and higher primary anastomosis rates compared with DT placement [1]. Interestingly, the total number of left-sided (LCC) colorectal cancer (CRC) cases in the studies included in the current meta-analysis was higher than the number of right-sided (RCC) CRCs (i.e. 259 vs. 55) [1]. This fact raises several molecular and cell biological issues regarding malignant colorectal obstructions.

Differences in clinical characteristics, treatment response, and prognosis based on disease sidedness (i.e. right-sided/RCC/or left-sided/LCC/colorectal cancer/CRC/) remain even among in patients with metastatic disease [2]. Usually, patients suffering from RCC less frequently require urgent surgery as compared to those with LCC. This is probably since patients with LCC more often develop symptoms of bowel obstruction [3]. According to recent findings, anatomy or stage at diagnosis alone cannot explain all the observed differences between left- and right-sided diseases. At the molecular level, significant discrepancies exist between LCC and RCC, which may be the explanation of all the apparent distinctness.

About the pathomechanism of cancer development, tumors originating from the left and right colons display obvious divergent in (epi)genotypes, gene, and protein expression profiles [2,4]. Chromosome instability (CIN) represents such a genomic inequality in which chromosomes are unstable, in a way that either whole chromosomes or parts of chromosomes are deleted or duplicated. The CIN pathway contributes to the emergence of nearly three-quarter of LCCs, while only to the one-third of RCCs. Microsatellite instability (MSI) is a consequence of somatic inactivation of the DNA mismatch repair genes due to promoter hypermethylation, leading to genetic hypermutability (predisposition to mutation). MSI results in the secondary widespread mutation of short repetitive DNA sequences (i.e. microsatellites), lack of DNA repair function, and thus accumulation of abnormal genes. MSI cancers predominantly occur in the right colon. It was also described that patients with MSI cancers had better survival rates as compared to those with microsatellite stable CRCs. CpG island methylator phenotype (CIMP) is an epigenetic control aberration results from the hypermethylation of cytosine at CpG islands in gene promoters. CIMP is important for gene inactivation in cancer cells. CIMP was found to be significantly associated with RCC [2,4].

Regarding the RAS (i.e. KRAS, NRAS) and BRAF genes, important components of the RAS-RAF-MAPK signal pathway, higher frequency of KRAS and BRAF mutations can be found in RCC than in LCC. Other genes also express differently based on the alteration of tumor location. NRAS and p53 mutation types (together with CIN) are more common in LCC than RCC. On the other hand, significant association between the CT genotype of SNP rs1800566 of the NADPH (nicotinamide adenine dinucleotide phosphate) gene and RCC is detectable. Several genes and proteins such as ERCC1 (excision repair cross-complementation group 1), GNAS (guanine nucleotide binding protein, alpha stimulating), telomerase, PODXL (podocalyxin-like protein 1), annexin A10, CTNNB1 (β1-catenin), and epiregulin are expressed predominantly in RCC. The overexpression of EGFR (epidermal growth factor receptor), TGF (transforming growth factor), topoisomerase I, and thymidylate synthase is characteristics mainly for LCC [2,4,5].

Many recent studies have shown the utility of microRNAs (miRs), a class of small non-coding RNAs, as cancer-related biomarkers, supported by the finding that some miRs display altered expression profiles in cancers compared to normal tissues. The post-transcriptional regulation of oncogenes and tumor suppressor genes by miRs displays location-associated differences in CRCs as well. In RCC, miR-31 is overexpressed, while in LCC miR-146a, miR-147b, and miR-1288 were found to be upregulated [4–6]. miR-31 is located at chromosome 9p21.3 and is reportedly deregulated in various human cancers. Regarding CRC, an association has been reported between miR-31, oncogenic potential, deeper invasion, and advanced disease stage. The miR-146a gene is located on chromosome 5q34. It acts as a modulator of the innate and adaptive immune responses. The miR-147b gene, which is located on chromosome 15q21.1, is involved in posttranscriptional regulation of gene expression by influencing both stability and translation of target mRNAs. It also participates in a negative feedback loop that can inhibit the proinflammatory response of macrophages to multiple Toll-like receptor ligand, miR-1288, is in 17p11.2 and can enhance cell proliferation and can alter major cell cycle events in colon cancer cells. According to recent results, it is plausible that different mechanisms regulating microRNA expression and consequently their target genes in left and right colon exist [4–6].

Additionally, distinct pathways dominate progression to relapse in left- and right-sided CRCs. V600E BRAF mutations are well demonstrated as conferring a worse prognosis in both metastatic and earlier-stage CRCs (mainly RCCs). Non-V600E mutations, however, are associated with favorable overall prognosis as compared to both BRAF wild-type and V600E BRAF-mutant cases. Interestingly, non-V600E BRAF mutations are less common in RCCs [7]. Overexpression of NOX4 (NADPH oxidase 4) and genes promoting stromal expansion, and downregulation of Wnt-initiating genes, are characteristics for relapse-prone LCCs. Contrariwise, RCC with high relapsing risk displays elevation in both the expression of Wnt-signaling and cell-cycle control genes, and downregulation of CDX2 (caudal type homeobox 2) and ITGA3 (integrin α3β1) [4,7]. Though CTNNB1 mutations rarely occur in CRC, their presence is associated with constitutive RAF-MEK-ERK pathway signaling, which may have relevance to disease prognosis [7].

Summarizing what has been described so far, based on the CIN, CIMP, and MSI status, the presence of gene mutations and epigenetic alterations, RCC and LCC can be considered as two distinct heterogeneous entities (Table 1). Moreover, these differences may lead to the suggestion that disease sidedness should be considered when making decisions regarding treatment modalities (e.g. endoluminal vs. emergency surgical decompression techniques) for patients with obstructing CRC.

TABLE 1. Molecular biological differences between RCC and LCC

Mechanisms of molecular carcinogenesis	RCC	LCC
Genomic alterations	MSI	CIN
Genetic alterations (consequential protein expression alterations)	KRAS, BRAF, NADPH, CTNNB1, ERCC1, GNAS, telomerase, PODXL, annexin A10, epiregulin, cell cycle control genes, Wnt-signaling, CDX2, ITGA3	p53, NRAS, EGFR, TGF, topoisomerase I, thymidylate synthase, genes promoting stromal expansion, NOX4 downregulation
Epigenetic alterations	CIMP, miR-31	miR-146a, miR-147b, miR-1288

Regarding the prognostic effect of preoperative obstruction, a multivariable analysis has revealed that acute/subacute obstruction adversely affected on the long-term prognosis in stage III colon and rectal cancer, but not in stage II CRC. Furthermore, preoperative obstruction seems to be associated with systemic recurrence, suggesting that micrometastasis may be present in these cases [8]. This is a very important point of view, as SEMS placement is not recommended as a standard treatment in malignant colorectal obstruction by the clinical guidelines from the European Society of Gastrointestinal Endoscopy [1]. One explanation of this decision is that the inferior long-term outcomes may be related to the radial pressure and consequential increased circulating tumor DNA concentration created by SEMS expansion [1].

Circulating cell-free DNA (cfDNA) in blood originates from different sources. Within inflammatory and tumorous conditions, cfDNA is especially derived from apoptotic or necrotic cells localizing the perivascular/perilymphatic area. However, circulating (tumor) cells disintegrating in the blood stream could serve as another source of cfDNA. Furthermore, cfDNA could be released from circulating lymphocytes via an active secretory pathway, and, additionally, contain pathogen (luminal microbiota)-derived nucleotide sequences.

It has been reported that SEMS placement may induce shedding of tumor cells into the circulation [9]. Circulating (disseminated) tumor cells are considered micrometastases. They can remain in a dormant state for many years after complete resection of the primary tumor before giving rise to macrometastasis [10]. Though the elevation of cfDNA levels in blood after SEMS expansion can be attributed, at least in part, to radial pressure and consequential tumor cell seeding, it should not be ignored that “pre-SEMS placement” circulating tumor cells and tumor infiltrating lymphocytes can also release their DNA into the blood circulation [10].

In sum, when SEMS placement is planned, the molecular and cellular biological aspects outlined above should be considered in addition to the patient’s clinical condition.

DISCLOSURE STATEMENT

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Additional information

Funding

Supported by the StartUp Program of Semmelweis University Faculty of Medicine (CO No.: 11720, Ikt.sz.: 5127/AOKGIE/2018; SE10332470). The funders had no role in data collection, decision to publish, or preparation of the manuscript.