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Review
. 2023 Jan 6:12:1023565.
doi: 10.3389/fonc.2022.1023565. eCollection 2022.

Liquid biopsy approaches and immunotherapy in colorectal cancer for precision medicine: Are we there yet?

Sheefa Mirza  1   2 , Kinjal Bhadresha  3 , Muhammed Jameel Mughal  4 , Michelle McCabe  5 , Reza Shahbazi  3 , Paul Ruff  1   2 , Clement Penny  1   2
Affiliations
Review

Liquid biopsy approaches and immunotherapy in colorectal cancer for precision medicine: Are we there yet?

Sheefa Mirza et al. Front Oncol. .

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths globally, with nearly half of patients detected in the advanced stages. This is due to the fact that symptoms associated with CRC often do not appear until the cancer has reached an advanced stage. This suggests that CRC is a cancer with a slow progression, making it curable and preventive if detected in its early stage. Therefore, there is an urgent clinical need to improve CRC early detection and personalize therapy for patients with this cancer. Recently, liquid biopsy as a non-invasive or nominally invasive approach has attracted considerable interest for its real-time disease monitoring capability through repeated sample analysis. Several studies in CRC have revealed the potential for liquid biopsy application in a real clinical setting using circulating RNA/miRNA, circulating tumor cells (CTCs), exosomes, etc. However, Liquid biopsy still remains a challenge since there are currently no promising results with high specificity and specificity that might be employed as optimal circulatory biomarkers. Therefore, in this review, we conferred the plausible role of less explored liquid biopsy components like mitochondrial DNA (mtDNA), organoid model of CTCs, and circulating cancer-associated fibroblasts (cCAFs); which may allow researchers to develop improved strategies to unravel unfulfilled clinical requirements in CRC patients. Moreover, we have also discussed immunotherapy approaches to improve the prognosis of MSI (Microsatellite Instability) CRC patients using neoantigens and immune cells in the tumor microenvironment (TME) as a liquid biopsy approach in detail.

Keywords: circulating cancer associated fibroblasts (cCAFs); colorectal cancer; exosomes; immune cells; liquid biopsy; mitochondrial DNA; neoantigen.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Liquid biopsy components in CRC and their clinical utility. CTCs are shedded from the tumor into the blood vessels where they can release their components: nucleic acids and exosomes with tumor-specific cargo material. For the analysis of these molecules, blood can be taken out, and plasma or serum further processed for the extraction of the desired constituents. From the blood circulation, these molecules can be filtered into saliva and urine which can also be collected and further analyzed. Each of these constituents delivers one or more levels of tumor information. The quantity of the concentration of single proteins or panels including numerous tumor proteins is the present gold standard in cancer management.
Figure 2
Figure 2
Overview of the CTCs detection technologies and the potential clinical applications of CTCs in CRC. CTCs isolation can usually be divided into two groups: physical isolation designed to exploit the differing physical belongings of blood components, such as size, deformity, and charge; and biological isolation, often utilizing antibody-based capture methods to enrich CTCs or deplete various blood cells. Following isolation, CTCs are open to a variety of downstream applications, focusing primarily on one of three categories: enumeration, characterization, and expansion.
Figure 3
Figure 3
Fundamental Functions and associated mechanisms of CAFs in CRC hallmarks. The figure shows the role of CAFs in CRC biology, including tumorigenesis, proliferation, angiogenesis, invasion and metastasis, stemness, therapy resistance, and tumor immunity.
Figure 4
Figure 4
Effects of CAFs in CRC. A numeral of biomarkers that are extremely expressed in CAFs, like α-SMA, fibroblast activation protein alpha (FAP), fibroblast-specific protein 1 (FSP-1), platelet-derived growth factor receptor-α (PDGFRα) and PDGFRβ have now been commonly used to classify or isolate CAFs from the pool of fibroblasts present in the whole body. Described genes and proteins showed poorer disease progression, recurrence-free survival, and overall survival. Taken together, these markers could be used as liquid biopsy approach for early detection and treatment prognosis in CRC patients.
Figure 5
Figure 5
Roles and application of exosomes. Tumor-derived exosomes promote cancer growth and metastasis. Through multiple mechanisms, they participate in cancer growth and metastasis by reshaping TME resulting into EMT, cell proliferation, apoptosis inhibition, immunosuppression, and angiogenesis. Exosomes derived from cancer cells are enriched with proteins, mRNA, miRNA, lncRNA, DNA etc. that are more abundant in cancer cells than in normal cells. Thus, exosomes may be used as biomarkers for cancer diagnosis, prediction, and treatment.
Figure 6
Figure 6
The impact of immune infiltrates on CRC. In CRC, immune infiltrates can impact CRC cell death, either directly or via tumoricidal T cells (TCT), and consequently affect tumor progression. For example, cytotoxic T cells, macrophages, and NK cells can exert a cytolytic effect on CRC cells. For other populations of cells, such as Treg, B cells, dendritic cells, or M2-like macrophages, generally impact CRC cell death by mediating the tumoricidal activity of TCT cells. Herein, Treg, regulatory B cells, immature dendritic cells, and macrophages enable TCT cells to be exhausted, thus causing substantial progression in CRC tumors. Accordingly, immunoscore system using immune cells could deliver insights into a novel liquid biopsy approach as a diagnostic tool.
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References

    1. Sawicki T, Ruszkowska M, Danielewicz A, Niedźwiedzka E, Arłukowicz T, rzybyłowicz KE. A review of colorectal cancer in terms of epidemiology, risk factors, development, symptoms and diagnosis. Cancers (Basel) (2021) 13(9):2025. doi: 10.3390/cancers13092025 - DOI - PMC - PubMed
    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin (2021) 71(3):209–49. doi: 10.3322/caac.21660 - DOI - PubMed
    1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin (2021) 71:7–33. doi: 10.3322/caac.21654 - DOI - PubMed
    1. Douaiher J, Ravipati A, Grams B, Chowdhury S, Alatise O, Are C. Colorectal cancer-global burden, trends, and geographical variations. J Surg Oncol (2017) 115(5):619–30. doi: 10.1002/jso.24578 - DOI - PubMed
    1. Xi Y, Xu P. Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol (2021) 14(10):101174. doi: 10.1016/j.tranon.2021.101174 - DOI - PMC - PubMed

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