Cancer exodus hypothesis

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The cancer exodus hypothesis establishes that circulating tumor cell clusters (CTC clusters) maintain their multicellular structure throughout the metastatic process. It was previously thought that these clusters must dissociate into single cells during metastasis. [1] According to the hypothesis, CTC clusters intravasate (enter the bloodstream), travel through circulation as a cohesive unit, and extravasate (exit the bloodstream) at distant sites without disaggregating, significantly enhancing their metastatic potential. This concept is considered a key advancement in understanding of cancer biology and CTCs role in cancer metastasis. [2] [3]

Contents

Mechanism

Traditionally, it was believed that CTC clusters needed to dissociate into individual cells during their journey through the bloodstream to seed secondary tumors. However, recent studies show that CTC clusters can travel through the bloodstream intact, enabling them to perform every step of metastasis while maintaining their group/cluster structure. [3] [2] [4]

The cancer exodus hypothesis asserts that CTC clusters have several distinct advantages that increase their metastatic potential:

Clinical relevance

The cancer exodus hypothesis offers important insights into how metastasis occurs and highlights the significance of CTC clusters in cancer progression. Detecting and analyzing CTC clusters through liquid biopsies could offer valuable information about the aggressiveness and metastatic potential of cancers. [10] [11] This information is particularly useful for identifying patients who may benefit from more aggressive treatment strategies. [2] [12]

Characterization

The hypothesis was developed due to several key studies, which have demonstrated the ability of CTC clusters to:

These findings underscore the critical role of CTC clusters in driving the metastatic cascade and suggest that CTC clusters could serve as important biomarkers in cancer diagnosis, prognosis, and treatment planning. [5] Additionally, understanding the mechanisms that allow CTC clusters to retain their structure and survive in circulation opens new avenues for targeted cancer therapies designed to disrupt this process. [15]

Future directions

As research into the cancer exodus hypothesis progresses, new therapeutic strategies could emerge to specifically target CTC clusters. Blocking their formation, disrupting their cohesion, or preventing their ability to survive in the bloodstream could offer new ways to prevent metastasis in aggressive cancers. Continued studies will be essential to further elucidate the biological pathways involved in CTC cluster-mediated metastasis and develop potential treatment interventions. [16] [17]

Related Research Articles

<span class="mw-page-title-main">Metastasis</span> Spreading of a disease inside a body

Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.

<span class="mw-page-title-main">Biopsy</span> Medical test involving extraction of sample cells or tissues for examination

A biopsy is a medical test commonly performed by a surgeon, an interventional radiologist, or an interventional cardiologist. The process involves the extraction of sample cells or tissues for examination to determine the presence or extent of a disease. The tissue is then fixed, dehydrated, embedded, sectioned, stained and mounted before it is generally examined under a microscope by a pathologist; it may also be analyzed chemically. When an entire lump or suspicious area is removed, the procedure is called an excisional biopsy. An incisional biopsy or core biopsy samples a portion of the abnormal tissue without attempting to remove the entire lesion or tumor. When a sample of tissue or fluid is removed with a needle in such a way that cells are removed without preserving the histological architecture of the tissue cells, the procedure is called a needle aspiration biopsy. Biopsies are most commonly performed for insight into possible cancerous or inflammatory conditions.

<span class="mw-page-title-main">Melanoma</span> Skin cancer originating in melanocytes

Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye.

The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. EMT has also been shown to occur in wound healing, in organ fibrosis and in the initiation of metastasis in cancer progression.

Anoikis is a form of programmed cell death that occurs in anchorage-dependent cells when they detach from the surrounding extracellular matrix (ECM). Usually cells stay close to the tissue to which they belong since the communication between proximal cells as well as between cells and ECM provide essential signals for growth or survival. When cells are detached from the ECM, there is a loss of normal cell–matrix interactions, and they may undergo anoikis. However, metastatic tumor cells may escape from anoikis and invade other organs.

<span class="mw-page-title-main">E-selectin</span> Mammalian protein found in Homo sapiens

E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene.

<span class="mw-page-title-main">Circulating tumor cell</span> Cell from a primary tumor carried by blood circulation

A circulating tumor cell (CTC) is a cancer cell from a primary tumor that has shed into the blood of the circulatory system, or the lymph of the lymphatic system. CTCs are carried around the body to other organs where they may leave the circulation and become the seeds for the subsequent growth of secondary tumors. This is known as metastasis, responsible for most cancer-related deaths.

<span class="mw-page-title-main">Desmoplasia</span> Growth of fibrous or connective tissue

In medicine, desmoplasia is the growth of fibrous connective tissue. It is also called a desmoplastic reaction to emphasize that it is secondary to an insult. Desmoplasia may occur around a neoplasm, causing dense fibrosis around the tumor, or scar tissue (adhesions) within the abdomen after abdominal surgery.

<span class="mw-page-title-main">Metastatic breast cancer</span> Type of cancer

Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer; there is no stage after IV.

Cancer is a category of disease characterized by uncontrolled cell growth and proliferation. For cancer to develop, genes regulating cell growth and differentiation must be altered; these mutations are then maintained through subsequent cell divisions and are thus present in all cancerous cells. Gene expression profiling is a technique used in molecular biology to query the expression of thousands of genes simultaneously. In the context of cancer, gene expression profiling has been used to more accurately classify tumors. The information derived from gene expression profiling often helps in predicting the patient's clinical outcome.

<span class="mw-page-title-main">The Hallmarks of Cancer</span> 2000 paper by Hanahan and Weinberg

The hallmarks of cancer were originally six biological capabilities acquired during the multistep development of human tumors and have since been increased to eight capabilities and two enabling capabilities. The idea was coined by Douglas Hanahan and Robert Weinberg in their paper "The Hallmarks of Cancer" published January 2000 in Cell.

<span class="mw-page-title-main">Cancer biomarker</span> Substance or process that is indicative of the presence of cancer in the body

A cancer biomarker refers to a substance or process that is indicative of the presence of cancer in the body. A biomarker may be a molecule secreted by a tumor or a specific response of the body to the presence of cancer. Genetic, epigenetic, proteomic, glycomic, and imaging biomarkers can be used for cancer diagnosis, prognosis, and epidemiology. Ideally, such biomarkers can be assayed in non-invasively collected biofluids like blood or serum.

<span class="mw-page-title-main">Tumor microenvironment</span> Surroundings of tumors including nearby cells and blood vessels

The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of cancer cells, stromal tissue and the extracellular matrix. Mutual interaction between cancer cells and the different components of the tumor microenvironment support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. The tumor microenvironment is in constant change because of the tumor's ability to influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

Single-cell sequencing examines the nucleic acid sequence information from individual cells with optimized next-generation sequencing technologies, providing a higher resolution of cellular differences and a better understanding of the function of an individual cell in the context of its microenvironment. For example, in cancer, sequencing the DNA of individual cells can give information about mutations carried by small populations of cells. In development, sequencing the RNAs expressed by individual cells can give insight into the existence and behavior of different cell types. In microbial systems, a population of the same species can appear genetically clonal. Still, single-cell sequencing of RNA or epigenetic modifications can reveal cell-to-cell variability that may help populations rapidly adapt to survive in changing environments.

<span class="mw-page-title-main">Circulating tumor DNA</span> Tumor-derived fragmented DNA in the bloodstream

Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the bloodstream that is not associated with cells. ctDNA should not be confused with cell-free DNA (cfDNA), a broader term which describes DNA that is freely circulating in the bloodstream, but is not necessarily of tumor origin. Because ctDNA may reflect the entire tumor genome, it has gained traction for its potential clinical utility; "liquid biopsies" in the form of blood draws may be taken at various time points to monitor tumor progression throughout the treatment regimen.

CAPP-Seq is a next-generation sequencing based method used to quantify circulating DNA in cancer (ctDNA). The method was introduced in 2014 by Ash Alizadeh and Maximilian Diehn’s laboratories at Stanford, as a tool for measuring Cell-free tumor DNA which is released from dead tumor cells into the blood and thus may reflect the entire tumor genome. This method can be generalized for any cancer type that is known to have recurrent mutations. CAPP-Seq can detect one molecule of mutant DNA in 10,000 molecules of healthy DNA. The original method was further refined in 2016 for ultra sensitive detection through integration of multiple error suppression strategies, termed integrated Digital Error Suppression (iDES). The use of ctDNA in this technique should not be confused with circulating tumor cells (CTCs); these are two different entities.

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Focused-ultrasound-mediated diagnostics or FUS-mediated diagnostics are an area of clinical diagnostic tools that use ultrasound to detect diseases and cancers. Although ultrasound has been used for imaging in various settings, focused-ultrasound refers to the detection of specific cells and biomarkers under flow combining ultrasound with lasers, microbubbles, and imaging techniques. Current diagnostic techniques for detecting tumors and diseases using biopsies often include invasive procedures and require improved accuracy, especially in cases such as glioblastoma and melanoma. The field of FUS-mediated diagnostics targeting cells and biomarkers is being investigated for overcoming these limitations.

Invasion and metastasis are fundamental hallmarks of cancer, representing the ability of the cancer cells to spread from their site of origin to distant tissues and organs. These processes are central to cancer's lethality, accounting for the majority of cancer - related deaths, and marking an important barrier to effective treatment.

References

  1. ↑ Ring A, Nguyen-Sträuli BD, Wicki A, Aceto N (February 2023). "Biology, vulnerabilities and clinical applications of circulating tumour cells". Nature Reviews. Cancer. 23 (2): 95–111. doi:10.1038/s41568-022-00536-4. PMC   9734934 . PMID   36494603.
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  4. 1 2 Au SH, Storey BD, Moore JC, Tang Q, Chen YL, Javaid S, et al. (May 2016). "Clusters of circulating tumor cells traverse capillary-sized vessels". Proceedings of the National Academy of Sciences of the United States of America. 113 (18): 4947–4952. Bibcode:2016PNAS..113.4947A. doi: 10.1073/pnas.1524448113 . PMC   4983862 . PMID   27091969.
  5. 1 2 Sayed ZS, Khattap MG, Madkour MA, Yasen NS, Elbary HA, Elsayed RA, et al. (April 2024). "Circulating tumor cells clusters and their role in Breast cancer metastasis; a review of literature". Discover Oncology. 15 (1): 94. doi:10.1007/s12672-024-00949-7. PMC   10984915 . PMID   38557916.
  6. ↑ Schuster E, Taftaf R, Reduzzi C, Albert MK, Romero-Calvo I, Liu H (November 2021). "Better together: circulating tumor cell clustering in metastatic cancer". Trends in Cancer. 7 (11): 1020–1032. doi:10.1016/j.trecan.2021.07.001. PMC   8541931 . PMID   34481763.
  7. ↑ Aceto N, Toner M, Maheswaran S, Haber DA (September 2015). "En Route to Metastasis: Circulating Tumor Cell Clusters and Epithelial-to-Mesenchymal Transition". Trends in Cancer. 1 (1): 44–52. doi:10.1016/j.trecan.2015.07.006. PMID   28741562.
  8. ↑ Sarioglu AF, Aceto N, Kojic N, Donaldson MC, Zeinali M, Hamza B, et al. (July 2015). "A microfluidic device for label-free, physical capture of circulating tumor cell clusters". Nature Methods. 12 (7): 685–691. doi:10.1038/nmeth.3404. PMC   4490017 . PMID   25984697.
  9. ↑ Allen TA, Cullen MM, Hawkey N, Mochizuki H, Nguyen L, Schechter E, et al. (2021). "A Zebrafish Model of Metastatic Colonization Pinpoints Cellular Mechanisms of Circulating Tumor Cell Extravasation". Frontiers in Oncology. 11: 641187. doi: 10.3389/fonc.2021.641187 . PMC   8495265 . PMID   34631514.
  10. ↑ Sarioglu AF, Aceto N, Kojic N, Donaldson MC, Zeinali M, Hamza B, et al. (July 2015). "A microfluidic device for label-free, physical capture of circulating tumor cell clusters". Nature Methods. 12 (7): 685–691. doi:10.1038/nmeth.3404. PMC   4490017 . PMID   25984697.
  11. ↑ Amintas S, Bedel A, Moreau-Gaudry F, Boutin J, Buscail L, Merlio JP, et al. (April 2020). "Circulating Tumor Cell Clusters: United We Stand Divided We Fall". International Journal of Molecular Sciences. 21 (7): 2653. doi: 10.3390/ijms21072653 . PMC   7177734 . PMID   32290245.
  12. ↑ Lawrence R, Watters M, Davies CR, Pantel K, Lu YJ (July 2023). "Circulating tumour cells for early detection of clinically relevant cancer". Nature Reviews. Clinical Oncology. 20 (7): 487–500. doi:10.1038/s41571-023-00781-y. PMC   10237083 . PMID   37268719.
  13. ↑ Cheung KJ, Padmanaban V, Silvestri V, Schipper K, Cohen JD, Fairchild AN, et al. (February 2016). "Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters". Proceedings of the National Academy of Sciences of the United States of America. 113 (7): E854 –E863. Bibcode:2016PNAS..113E.854C. doi: 10.1073/pnas.1508541113 . PMC   4763783 . PMID   26831077.
  14. ↑ Allen TA, Gracieux D, Talib M, Tokarz DA, Hensley MT, Cores J, et al. (January 2017). "Angiopellosis as an Alternative Mechanism of Cell Extravasation". Stem Cells. 35 (1): 170–180. doi:10.1002/stem.2451. PMC   5376103 . PMID   27350343.
  15. ↑ Taftaf R, Liu X, Singh S, Jia Y, Dashzeveg NK, Hoffmann AD, et al. (August 2021). "ICAM1 initiates CTC cluster formation and trans-endothelial migration in lung metastasis of breast cancer". Nature Communications. 12 (1): 4867. Bibcode:2021NatCo..12.4867T. doi:10.1038/s41467-021-25189-z. PMC   8358026 . PMID   34381029.
  16. ↑ Allen TA (March 2024). "The Role of Circulating Tumor Cells as a Liquid Biopsy for Cancer: Advances, Biology, Technical Challenges, and Clinical Relevance". Cancers. 16 (7): 1377. doi: 10.3390/cancers16071377 . PMC   11010957 . PMID   38611055.
  17. ↑ Khoo BL, Grenci G, Lim YB, Lee SC, Han J, Lim CT (January 2018). "Expansion of patient-derived circulating tumor cells from liquid biopsies using a CTC microfluidic culture device". Nature Protocols. 13 (1): 34–58. doi:10.1038/nprot.2017.125. PMID   29215634.
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