Background

Colorectal cancer (CRC) is the world’s second leading cause of cancer deaths, and liver metastasis from CRC accounts for the majority of fatalities in CRC patients [1, 2]. CRC’s most common target metastatic sites are the liver, lung, bone, and brain, known as organ tropism, and the liver is the most common site of CRC metastasis [3]. Up to 50% of CRC patients have liver metastasis, and approximately 15–23% of patients have metastasis at the time of diagnosis. Hepatic resection combined with modern adjuvant systemic regimens is only effective in 20% of colorectal cancer liver metastasis (CRLM) patients. Even after curative hepatic resection, the 5-year overall survival rate is around 48% [4]. In practice, however, approximately 80% of CRLM patients have unresectable metastatic lesions [5, 6].They are typically downstaged by systemic and local therapy (including stereotactic radiotherapy, transarterial radioembolization, and transarterial chemoembolization) to achieve metastatic liver lesion resection, improving patients’ long-term survival and prognosis. Although the development of adjuvant systemic therapy has significantly improved the clinical outcome of patients with stage IV CRC liver metastases [7], early detection of CRLM remains critical to good results. Despite the high resolution of computed tomography (CT) as the most commonly used detection modality, up to 30% of liver metastasis cannot be detected in their early stages. MRI and PET-CT may have higher sensitivity and specificity, but the costs are prohibitive [2].

Many studies have found that cancer metastasis is a complex selective process influenced by anatomical, biological, and microenvironmental factors [8]. Theories such as “seed-soil,” pre-niche, and the crosstalk between tumor cells and immune cells provide direct evidence for metastatic propensity and organ-specific tropism of metastatic cancer cells, implying that metastasis is a process that is dependent on organ-targeted anchoring characteristics [9,10,11]. Thus, investigating how metastatic CRC appears, when it appears, and the underlying mechanism provides clues for the treatment of CRC and its liver metastasis.

Theories underlying organ-specific metastasis process

According to a traditional model of metastatic spread, cancer cells undergo the following general steps known as metastatic cascade, which can be divided into two major phases: (1) dissemination from the primary lesion to distant organs by entering systemic circulation and adapting to a new microenvironment (intravasation, extravasation), and (2) colonization followed by expanding growth [12]. The multi-step process typically involves an invasion-metastasis cascade. According to Hanahan and Weinberg, the hallmark of “activating invasion and metastasis” is one of the six important features of cancer. Invading cancer cells pass through or collaborate with stroma to avoid elimination by immune system cells such as neutrophils, monocytes/macrophages, and endothelial cells. Epithelial-mesenchymal transition (EMT) program can be activated by carcinoma cells and orchestrate most steps of invasion and metastasis, except for colonization. Disseminated tumor cells act in dormancy in circulation and new environment tissue to avoid immune surveillance, and then they interact with the tissue microenvironment to be awakened from dormancy. Moreover, the development of metastatic colonization needs multiple biological programs, and these adaptations require intrinsic capabilities of cancer cells and a permissive tumor microenvironment with stromal support cells. The invasion-metastasis process, which appears to be a linear progression from the primary tumor to metastatic colonies, operates under the guidance of a specific paradigm [13,14,15]. However, several studies have suggested that metastasis cannot be defined solely by chronological order, as many interdigitated and mutually exclusive metastasis events do not appear to follow a linear progression model [16]. In our understanding of CRC metastasis to the liver, the general “seed and soil” theory and the “mechanistic theory” are highly complementary [17]. Anatomically, CRC metastasis is thought to occur in a stepwise fashion, with the majority of venous drainage from the intestine entering the portal system to flow into the liver, and then the disseminated cells in the bloodstream are arrested by the first available liver capillary beds with endothelial cells and basement membrane [18]. Although the physical characteristics influence organ tropism and affect the non-random organ-specificity, the fact is that organs receiving similar blood volumes have distinct metastatic-formation efficacy. The special ability of circulating tumor cells to form secondary growth cannot be explained as purely mechanistic [19, 20]. Cancer cells entering the circulation disperse in various directions, but their anchorage to specific metastatic sites is determined by various factors [21]. Stephen Paget proposed a hypothesis in 1889 that described cancer cells as “seeds” and receptive microenvironments as “soils,” both of which are required for rate-limiting steps in the formation of micrometastasis [9]. Recently, growing evidence for the process of pre-metastatic niche formation adds new insights to the “seed-soil” theory. For example, metastasis-initiating cells co-opt the metastatic microenvironment to facilitate colonization. Before cancer cells disseminate from the primary tumor, a subpopulation of primary tumor cells has the “prime” potential and reprograms the distant microenvironments [22]. Pre-metastatic niche formation is important in CRLM. By recruiting various cellular components (Kupffer cells, macrophages, and fibroblasts), producing CRC-derived factors (chemokines and cytokines) and exosomes, primary CRC prepares a favorable microenvironment in the liver. It mediates liver-target metastasis [23, 24]. As a result, the concept of pre-metastasis niches may trump the chronological metastasis pattern that is dependent on circulation. Recently, many discoveries have clarified the key molecules and cells involved in liver-specific metastasis of CRC. For example, LINC00485 is a newly discovered class of Long non-coding RNAs (lncRNAs), and low expression of LINC00485 predicts a poor prognosis for CRC patients. LINC00485 attenuated CRC cell invasion and liver metastasis by directly modulating the miR-581/EDEM1 axis. Overexpression of LINC00485 enhanced the expression of epithelium markers E-cadherin and significantly down-regulated the expression of mesenchymal markers N-cadherin, indicating a loss of malignant phenotype in cancer cells [25]. Higher levels of tumor suppressor microRNAs (miR-25-3p, miR-130b-3p, miR-425-5p, miR-934) in the exosomes were secreted by CRC cells in more advanced disease, and these exosomal miRNAs induced macrophages M2 polarization to promote liver metastasis of CRC. CXCL13 secreted by M2-polarized macrophages promoted the transcription of exosomal miR-934 in CRC cells, forming a positive feedback loop to foster CRLM [35]. The relative timing of metastatic spread is determined by comparing the genetic divergence between the primary tumors and metastasis. In the classic “linear evolution model,” the metastasis-initiating clone(s) emerge late in the primary tumor and seed at the metastatic sites as a byproduct of tumor development. Instead, in the “parallel evolution model,” the metastatic subclone(s) spread from the primary tumor to distant sites early, and both the primary and metastatic subclones evolve concurrently. As a result, compared with the “linear evolution model,” a greater degree of Primary-Metastasis genetic divergence is expected in the “parallel evolution model” [36]. In addition to the time of metastasis, studies of the clonal relationship between primary tumors and metastases explained metastatic seeding patterns based on genomic data analysis: identification of monoclonal/polyclonal metastasis and monophyletic/polyphyletic metastasis may provide information for treatment improvement. In metastatic CRC, both monoclonal/polyclonal metastasis and monophyletic/polyphyletic seeding patterns were observed. Polyclonal metastasis appeared to be the most common type of CRC metastasis. A polyphyletic seeding pattern was observed in the case of CRC with liver metastasis followed by lung metastasis [37, 38]. For the distinct routes of metastasis, Hai-ning et al. investigated the genomic evolution for the clonal origin and revealed three metastatic models (sequential, branch-off, and diaspora) by phylogenetic reconstruction using Treeomics. The results of the genomic analysis showed that liver and lung metastasis might originate from primary tumors independently rather than subsequently, providing genomic evidence for the organotropisms of metastatic CRC cells. However, the relationship between the characteristics of primary site subclones and their potential for liver metastasis has not been thoroughly investigated [38].

The underlying molecular mechanisms and contributing factors involved in CRLM

Genetic and epigenetic changes associated with liver metastasis of CRC

Cancer cells are thought to acquire metastatic capacity due to genetic and epigenetic changes. Genetic mutations can potentially disrupt epigenetic patterns, and the interaction between these two mechanisms can promote metastasis. [33, 39,40,41,42].

Although numerous genetic alterations have been detected between the primary tumor and metastatic sites in CRC [43,44,45], much remains unknown about the interaction between tumor genomic features and metastatic potential and organ-specific metastatic patterns [34, 46]. The clonal relationship observed between paired primary tumors, and metastasis explains at least part of the dissemination of metastasis-competent clones in different temporal patterns and trajectories [36, 47, 48]. This section will will sort out the genetic/epigenetic alterations associated with CRC liver-specific metastasis and summarize recent studies on the metastatic evolution patterns (temporal patterns and routes) observed in the metastatic CRC cohort.

Genetic alterations associated with liver metastasis of CRC

Several whole-genome sequencing analyses on metastatic tumors have been performed in recent years to gain insight into the critical genetic events involved in CRLM. Several studies have been conducted to investigate single nucleotide variations (SNVs), mutated genes, and chromosome copy numbers of CRLM. An analysis of metastatic solid tumor genomes revealed that consistent genetic changes indicate cancer metastasis remains to be further identified [44]. A pan-cancer cohort study of 25,000 patients’ tumor genomic profiling identified the associations between genetic alterations and metastatic patterns in 50 tumor types. The result showed that copy number alterations were not significantly associated with the metastatic burden for CRC. Chromosomal instability may be established early in tumor development and was already high in patients with low metastatic burden [45]. Oga et al. discovered 6855 mutations in primary CRC tumors without liver metastasis, primary metastatic CRC, and paired liver metastasis (LM) lesions using whole-exome sequencing (WES) analysis. The result showed that the somatic genomic profiles of primary CRC tumors and LM lesions were not significantly different; however, LM regions showed an enriched A-to-C nucleotide conversion in the context of “AAG,” an event that may be specific to liver metastases [49]. Li et al. used WES to look for somatic SNVs (sSNVs) in primary tumors and matched liver metastasis samples from 16 CRC patients with liver metastasis. The SNVs data were analyzed using ABSOLUTE software to calculate the proportion of mutational genes in each sample. An average of 34% (8–63%) mutations were shared by both primary tumors and liver metastasis, indicating a common ancestral trunk among them. Furthermore, an average of 34% (12%–88%) mutations were metastasis-private, which may be a result obtained or lost during the tumor metastasis process. The probable timing order of mutation events has been investigated by analyzing the distribution of cancer cell fractions (CCF). A higher median CCF value indicates that the mutation occurred earlier. Data on the median CCF value of TP53 and KRAS showed that TP53 mutations occurred earlier than KRAS in primary tumors but later than KRAS in liver metastasis [50].

Several studies have been conducted to identify frequently mutated genes involved in metastasis. For example, 707 genes have been identified as LM-associated genes, which specifically mutated in the LM regions but not in CRC tumors without liver metastasis, including ADAMTS10, NELL1, and RXFP3, implying their roles in liver metastasis. Furthermore, ADAP1 fusions were discovered in the RNA-seq dataset, indicating that ADAP1 was fused to GET4, SUN1, or NOC4L in an out-of-frame manner in the LM region. Two in-frame fusions of the ADAP1’s ArfGAP domain with proteins from GEMIN4 and TMEM8A have been discovered, which may facilitate metastasis by activating GTPase [49]. A study used targeted sequencing of primary tumors and matched liver metastasis samples to describe the genome landscape of Chinese CRLM patients. The most frequently mutated genes were found to be TP53 (324/396, 82%), PC (302/396, 76%), KRAS (166/396, 42%), SMAD4 (54/396, 14%), FLG (52/396, 13%), and FBXW7 (43/396, 11%). Furthermore, the distribution of genomic changes was related to the time of metastasis (synchronous/metachronous liver metastasis). Alterations in genes of FBXW7, FLT3, XIRP2, TSC2, LATS1, and CREBBP were significantly enriched in metachronous lesions, and alterations in CDK12 were significantly enriched in synchronous LM [51].

The differences in chromosome copy number between primary and secondary tumors revealed that genetic aberrations in liver metastasis are a dynamic process, such as the presence of a focal amplification of chromosome 7p in primary tumors but not in the LM region. The loss or gain of copy number variations (CNVs) most likely allows clones to be more fit in a new environment [49]. Anand and colleagues investigated the link between aneuploidy and CRC metastasis. Aneuploidy is not just a byproduct of chromosomal instability; it has a direct influence on cancer cells’ metastatic capability, either promoting or inhibiting metastasis behavior. HCT116 colon cells with an extra copy of chromosome 5 exhibit increased invasive behavior by activating an EMT program and upregulated matrix metalloproteinases (MMPs) [52]. In addition, CNV alterations, as a common biological event during tumor progression and therapy, usually involve multiple genes. There are potentially complex interactions between co-amplified or co-deleted genes affected by CNV events, acting as a whole. It has been reported that CDK12 and HER2 were frequently co-amplified in CRC, and inhibition of CDK12 can enhance the sensitivity of CRC cells to lapatinib, an anti-HER2 tyrosine kinase inhibitor (TKI) [53].

Genome events related to metastatic evolution pattern

According to phylogenetic analysis of non-synonymous SNVs from the primary tumor and metastatic liver lesions, there were three main clonal evolution patterns from primary to liver metastases: clonal-clonal pattern (C–C) (early events), subclonal-clonal pattern (S–C) (middle-stage events), none-clonal pattern (0-C) (later events). In terms of CNV events, Chr 20q amp, 17p del, 18q del, and 8p del in clonal- clonal evolution were considered as early events, 8q amp in liver metastasis-specific evolution was considered as later events, and 8q amp, 13q amp, and 8p del in subclonal-clonal evolution were considered as middle-stage events. SYNE1 was a mutant gene with S–C clonal evolution characteristics. Its mRNA expression level in normal, CRC primary, and liver metastasis gradually decreased; however, its functional mechanism in CRLM remains unknown [50]. Tumor mutation burden, an immunotherapy biomarker, in conjunction with HLALOH (HLA, Human leukocytes antigens, LOH, Loss of heterozygosity), is used as an indicator to assess the efficacy of immunotherapy [54]. Subclonal mutation loads were higher in primary tumors than in clonal mutation loads. In contrast, the proportion of clonal mutation was increased in metastatic lesions, which is consistent with the S–C evolutionary pattern, indicating the role of selection in metastasis. HLA LOH occurred in samples with recurrent mutations of S–C changing pattern, including KRAS, SYNE1, FBXL2, DNAH11, and CACNA1H, indicating that this mutational clonal pattern promotes CRC cells evading the immune system during liver metastasis [50].

Epigenetic modifications associated with liver metastasis of CRC

No genetic changes have been identified as consensus metastasis-specific drivers in the process of CRC metastasis. However, epigenetic changes may provide an alternative mechanism to induce tumor cells for metastatic phenotypes [55]. The core content of epigenetic modification is the covalent modification of histones and nucleic acids (including methylation, acetylation, ubiquitination, etc.). In addition, epigenetic regulation also includes chromatin remodeling and transcriptional mediators (mainly non-coding RNAs, such as microRNAs and long ncRNAs) of the RNA splicing machinery. They affect gene expression without sequence changes in DNA [56, 57] (Fig. 2). Epigenetic changes play an important role in CRLM (Table 1), but whether there are metastasis-specific epigenetic drivers and their mechanism need to be investigated further [40].

Fig. 2
figure 2

The role of epigenetic modifications in CRC liver metastasis. Epigenetic modification plays a vital role in gene regulation, mainly for various covalent modifications of histones and nucleic acids. The change of nucleic acid is in DNA and RNA. In addition, epigenetic modification also includes chromatin remodeling, non-coding RNA regulation, and other mechanisms. DNA methylation mainly occurs at the C of 5′-CpG-3′ to generate 5-methylcytosine (5mC). Under the action of DNA methyltransferase (DNMT), methyl groups are covalently bonded to the 5' carbon of cytosines of CpG dinucleotide residues. Hypermethylated gene expression is suppressed. Chromatin remodeling can regulate gene expression by regulating chromatin changes in chromatin structure and location, such as PU.1 opening chromatin regions of downstream effector genes and recruiting additional epigenetic modifiers to regulate gene expression. N6-Adenylate methylation (m6A), which inserts a methyl substituent on the N atom at the 6-position of adenosine. During transcription, m6A deposited on RNA transcripts affects gene expression post-transcriptionally by altering the structure of RNA or the specific recognition of m6-binding proteins. Non-coding RNAs are endogenous RNA molecules that cannot be translated into proteins but have particular gene expression regulatory functions, regulating post-transcriptional gene expression by complementary binding to RNA transcripts of the target gene

Full size image
Table 1 Epigenetic modification in CRC liver metastasis
Full size table

Dysregulation in DNA methylation is the mainly studied DNA modification in tumor and metastasis [64]. The methylation changes of primary CRC, metastatic CRC, and liver metastases differ between individuals. CRC primary tumors exhibited global hypomethylation and CpG island (CGI) hypermethylation compared to healthy tissues, whereas metastatic colorectal lesions exhibit high-level global methylation but lower CGI methylation [65]. The study by Udali et al. came to the same conclusion. Primary CRC and synchronous liver metastases had similar epigenetic DNA hypomethylation status when compared with homologous cancer-free colon tissues, indicating that these epigenetic mechanisms occurred in the early stages of CRC development and were maintained till the stage of liver metastasis progression [66]. However, the mechanism by which methylation inhibits tumor suppressor gene expression may be compromised during metastasis. Mahdi et al. discovered that the regulatory mechanism of methylation on gene expression might be compromised during the process of CRC tumor cell metastasis and colonization in the liver. The expression levels of three endothelin system genes changed significantly during the liver colonization of CC531 cells. When metastatic cell lines were exposed to Decitabine (DAC, which inhibits DNA methyltransferases), the expression of endothelin system genes did not increase, indicating that these gene expression changes were not caused by DNA methylation. This suggests that the regulatory function of epigenetic alterations may be gradually lost in the late stage of metastasis [67]. The microenvironment-induced epigenetic mutation is an essential mechanism for metastatic tumor cells to grow in their new niche. The hepatic growth factor (HGF) is abundant in the microenvironment of liver metastases. HGF from the metastatic liver microenvironment was shown to activate the c-Met/PI3K/AKT/mTOR axis in CRC cells, activating the SREBP2-dependent cholesterol biosynthesis pathway to promote CRC liver metastasis [68]. PU.1 is a pioneer factor that remodels chromosomes by opening the enclosed chromatin and enlisting the help of additional epigenetic modifiers. According to one study, HGF caused PU.1 phosphorylation in metastatic cells. The phosphorylated PU.1 regulated downstream regulatory elements to activate the effector gene DPP4. The HGF/PU.1/DPP4 axis was activated, which promoted the growth of CRC tumor cells at the site of the liver. Targeting the chromatin remodeling pathway in the future may provide additional treatment options for metastatic cancer [

Availability of data and materials

All data included in this study are available upon request by contact with the corresponding author.

Abbreviations

CRC:

Colorectal cancer

CRLM:

Colorectal cancer liver metastasis

SNVs:

Single nucleotide variations

sSNVs:

Somatic single nucleotide variations

LM:

Liver metastasis

CCF:

Cancer cell fractions

EMT:

Epithelial-mesenchymal transition

CNVs:

Copy number variations

MMPs:

Matrix metalloproteinases

TKI:

Tyrosine kinase inhibitor

C–C:

Clonal- Clonal

S-C:

Subclonal- Clonal

0-C:

None- Clonal

HLA:

Human leukocytes antigens

LOH:

Loss of heterozygosity

CGI:

CpG island

HGF:

Hepatic growth factor

m6A:

N6-methyladenosine

Circ RNAs:

Circular RNAs

LncRNAs:

Long non-coding RNAs

CYTOR:

Cytoskeleton regulator RNA

CSC:

Cancer stem cell

MCSCs:

Migrating CSCs

TA:

Transient amplification

TICs:

Tumor- initiating cells

LGR5:

LT-TICs: long term tumor- initiating cells G-protein-coupled receptor 5

ISC:

Intestinal stem cell

MDSCs:

Myeloid- derived suppressor cells

S1PR1:

Sphingosine 1-phosphate receptor 1

STAT3:

Signal transducer and activator of transcription 3

CAFs:

Cancer-related fibroblasts

BMP:

Bone morphogenetic protein

NOD:

Nucleotide-binding oligomerization domain 1

LSMCM:

LPS-stimulated Monocyte Conditioned Medium

IM:

Inflammatory monocytes

DC:

Dendritic cell

aCGH:

Array-based comparative genomic hybridization

3'-UTR:

3'-Untranslated region

lncRNAs:

Long non-coding RNAs

CTC:

Circulating tumor cell

circRNAs:

Circular RNAs

pre-Micro RNA:

Pre-miRNAs

FLT3LG:

Fms-related tyrosine kinase 3 ligand

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Acknowledgements

Not applicable.

Funding

This work was financially supported by grants from the National Key Research and Development Program of China (2021YFF1201300, 2022YFE0103600), the National Natural Science Foundation of China (No. 81872280, 82073094), the CAMS Innovation Fund for Medical Sciences (CIFMS)(2021-I2M-1-014), the Open Issue of State Key Laboratory of Molecular Oncology (No. SKL-KF-2021–16), and the Independent Issue of State Key Laboratory of Molecular Oncology (No. SKL-2021–16).

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Authors and Affiliations

  1. Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Bei**g, 100021, China

    Yaru Niu, Wenwei Yang & Yongkun Sun

  2. National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang, 065001, China

    Yongkun Sun

  3. New Research Building, National Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Bei**g, 100021, China

    Haili Qian

Authors
  1. Yaru Niu
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  2. Wenwei Yang
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  3. Haili Qian
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  4. Yongkun Sun
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Contributions

YN have drafted the work and substantively revised it. WY contributed to the literature review. HQ and YS contributed to the supervision and supported final approval of the article. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Haili Qian or Yongkun Sun.

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Niu, Y., Yang, W., Qian, H. et al. Intracellular and extracellular factors of colorectal cancer liver metastasis: a pivotal perplex to be fully elucidated. Cancer Cell Int 22, 341 (2022). https://doi.org/10.1186/s12935-022-02766-w

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