Biological and Clinical Characteristics of Proximal Colon Cancer: Far from Its Anatomical Subsite

Abstract

Colorectal cancer is a heterogeneous disease which can be divided into proximal colon cancer, distal colon cancer and rectal cancer according to the anatomical location of the tumor. Each anatomical location of colorectal cancer exhibits distinct characteristics in terms of incidence, clinical manifestations, molecular phenotypes, treatment, and prognosis. Notably, proximal colon cancer differs significantly from cancers of other anatomical subsites. An increasing number of studies have highlighted the presence of unique tumor biological characteristics in proximal colon cancer. Gaining a deeper understanding of these characteristics will facilitate accurate diagnosis and treatment approaches.

Keywords: Colorectal cancer; Gut microbiota; Proximal colon cancer; Right-sided colon cancer; Tumor biology.

Figure 1

Anatomical subtypes of colorectal cancer and their associations with epidemiological features, clinical features and tumor molecular features. The colorectum is anatomically divided into three segments: the proximal colon, which extends from the caecum through the ascending colon to the transverse colon; the distal colon, consisting of the descending colon and sigmoid colon; and the rectum. Colorectal cancer (CRC) exhibits etiological heterogeneity based on tumor location. Demographically, proximal colon cancer is more prevalent in women, older individuals, and white and black populations; distal colon cancer occurs more frequently in men and younger individuals; while rectal cancer is predominant among early-onset cases (diagnosed before age 50 years) and Asian populations. In terms of tumor molecular markers, proximal colon cancer shows enrichment for subtypes characterized by microsatellite instability-high status (MSI-H), CpG island methylator phenotype-high status (CIMP-H), BRAF mutation, or RAS mutation; whereas distal colon cancer is associated with chromosomal instability (CIN)-positive subtype. Understanding the epidemiological trends of proximal colon cancer helps contextualize its distinct clinical presentations.

Figure 2

Canonical molecular pathways underlying the initiation and progression of proximal colon cancer Proximal colon cancer typically arises from adenoma or serrated neoplasia. As depicted in the figure, pathway 1 illustrates the commonly mutated genes and molecular pathways involved in the progression from adenoma to carcinoma, while pathway 2 represents those associated with the progression from serrated neoplasia to cancer. Notably, during the dysplasia stage, the Wnt signaling pathway predominantly operates as a key molecular pathway; APC exhibits closer association with carcinogenesis mechanisms linked to adenoma, whereas β-catenin is more closely related to those associated with serrated neoplasia. In both adenoma and serrated neoplasia stages, HER-2 signaling pathway plays significant role. Mutations in NRAS and KRAS are particularly relevant to adenoma-associated carcinogenesis, whereas KRAS and BRAF mutations are more closely tied to serrated neoplasia. During cancer progression, major molecular pathways include EGFR signaling and TGF-β signaling pathways. Among these, SMAD4 demonstrates stronger correlation with adenoma's carcinogenesis mechanism while PIK3CA and PTEN exhibit closer associations with serrated neoplasia's carcinogenesis mechanism.

Figure 3

Four key mechanisms of gut microbiome associated with the occurrence and progression of colorectal cancer a. The inflammation pathway triggered by toxins secreted by the gut microbiome, such as Salmonella or E. coli, can lead to chronic inflammation and an increase in reactive oxygen species (ROS) within the mucosal lining, resulting in DNA damage. b. Tumor microenvironment (TME): Certain microorganisms like Fusobacterium nucleatum and Bacteroides fragilis have the ability to modulate the density of different types of T cells, creating a tumor microenvironment that promotes tumor initiation and progression. c. Bacterial components can promote tumor cell proliferation through the NF-κB pathway, for example, via putative cell wall binding repeat 2 (PCWBR2) surface protein produced by Peptostreptococcus anaerobius. d. Senescence and tumor growth can be facilitated by specific strains of E. coli that produce colistin-encoded enzymes responsible for hepatocyte growth factor (HGF) synthesis.

Figure 4

Relevance of metabolites in the initiation and progression of colorectal cancer Primary bile acids can undergo enzymatic cleavage by gut microbiota, particularly anaerobic colonic microbes, to form secondary bile acids. These secondary bile acids are subsequently passively reabsorbed into epithelial cells where they can induce an increase in reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to DNA damage in colonic epithelial cells and promoting the initiation of CRC. CRC cells respond by upregulating endogenous lipogenesis and cholesterol synthesis to support their proliferation, including activation of β-oxidation of endogenous lipids and cellular respiration. These metabolic alterations activate fatty acid synthetase (FASN) through the mTOR pathway, enabling saturated fatty acids (SFA) incorporation into the cancer cell phospholipid membrane, thereby reducing susceptibility to free radicals and therapeutic drugs. This tumorigenic process may facilitate tumorigenesis and metastasis.