Cancer metastasis is the leading cause of death in patients, with circulating tumor cells (CTCs) believed to be the metastatic precursors that are expelled from the primary tumor or metastatic deposits and circulate in the blood.

The detection and treatment of malignant cancers remains largely ineffective due to heterogeneity between patients and within the tumor, as well as the ability of cancer cells to spread locally or remotely through metastatic progression, resulting in treatment failure and high mortality Therefore, there is an absolute need for disruptive medical technologies that can achieve a more reliable cancer diagnosis, higher therapeutic efficacies and more favorable long-term clinical benefit;

Cancer metastasis is considered a multi-stage  process with distinct  signaling  pathways at each stage Includes:

(1) local invasion of primary tumor cells in neighboring locations;

(2) endovascularization: migration into nearby blood vessels

(3) transient travel and survival in the bloodstream of a population known as “circulating cancer cells (CTCs)”

(4) extravasation: CTRs travel out of the blood vessel and seeds to distant organs

(5) colonization and development in remote locations, which eventually become clinically detectable metastatic tumors. During this process, many metastatic lesions may be present as micro-metastases for a long time, which is difficult to detect clinically, but appears to be responsible for the eventual relapse of the disease.

Tumors are constantly evolving with dynamic genetic and epigenetic changes during the transition from one primary tumor in metastases. Although primary tumor biopsies are relatively accessible, they offer very limited information on the behaviors of metastatic tumors, which are often difficult to obtain by surgery. Unfortunately, most of our current therapeutic strategies are based on molecular and pathophysiological information derived from primary tumors CTCs, a single group of tumor cells created by tumors  [excreted by primary or metastatic deposits and entering the bloodstream]are metastatic precursors that create distinct metastatic populations.

CTCs could be accessible through simple blood sampling and thus can be accessible through simple blood collections  and thus can be accessible through simple blood collection offer as a “liquid biopsy” in real time to detect the biological progressions of the cancer during its transition to metastases.

TCCs are extremely rare, about one in billion blood cells can be CTCs. This has imposed a significant technical challenge on effective isolated CTCs.

TCCs are believed to be pre-metastatic populations that cause distant metastases, so a full understanding of the biology of CTC may promise to devise new therapeutic strategies Primary tumor biopsy analyses may only reveal signatures limited to local tumors, which may have undergone dramatic molecular remodeling during metastatic evolution. Liquid biopsy technologies based on CTCs  could  allow for a highly personalized treatment of cancer. An individual tumor biopsy often does not represent the set of heterogeneous tumors leading to relapse . On the other hand, CTCs collected from different stages of treatment may reveal the evolving characteristics of the tumor and possibly record the dynamic progression of the tumor.

Other liquid biopsies, such as circulation volume DNA (ctDNA) and exosomes, may similarly serve the purpose of guiding therapeutic decisions when detecting and treating cancer

Immunochargmentation and enumeration of CTCs remain effective in predicting disease progression and therapeutic response to various types of cancer , but  recent technological revolutions in microfluid mechanics techniques and single-cell studies are beginning to reveal the molecular “dark matter” of these populations of “metastatic precursors”. Using analyses of a high-resolution cell, it is now possible to systematically create profiles of the genome, transcription and primate of individual CTCs.

Genomic and transcriptional studies have revealed significant heterogeneities between individual CTCs and subpopulations of CTCs, in a way that may reflect the polyclonal origin of their tumors. Molecular analyses of these cells further identified the correlation between activation of abnormal WNT signaling in CTC subsectors and therapeutic resistance  in patients treated with AR  inhibitors in prostate cancer.Other  researchers using series of breast CTC as  well as CTCs isolated from patients with breast cancer [ER+and -HER2]identified heterogeneous CTC populations that coexisted either as her2 + subsectors  Or HER2-.It is noteworthy that these two subtypes of CTCs were guided by oncogenic signaling and can be intermodal during differential treatment. The simultaneous targeting of both HER2 + and HER2- CTC populations using inhibitors that block both pathways resulted in the elimination of oncogenesis caused by CTCs.These studies collectively demonstrated the strength of biological CTC characterizations in monocytar levels in deciphering cancer heterogeneities and metastatic tropisms

It was first discovered that in some breast cancer patients CTCs traveled along with white blood cells within circulation called “clusters of CTCs” DNA methylation analyses of individual CTC and CTCs clusters revealed submethylated areas that were selectively occupied by the key transcription agents OCT4, NANOG, SOX2 and SIN3A, which  play critical roles in the metastatic sowing of CTC clusterss.Further single cell studies of white blood cells related to CTC had identified an unexpected role of neutrophils in promoting the proliferation of CTC clusters and metastatic colonization . Other heterotypical interactions of TC with other non-CTC cells, such as cancer-related stromal cells, fibroblasts and certain types of immune cells were also reported to have a significant impact on CTC survival or metastatic Colonization. strain transfer agents

Conclusion and  Perspectives

Recent developments in microfluents allow for the effective isolation of viable TCCs that could be multiplied by ex vivo culture and in vivo animal models.A cell’s sequencing technologies have significantly accelerated the biological discoveries of TCCs.

This comprehensive understanding of CTC biology is critical to devising effective  CTC biomarkers for personalized monitoring and diagnosis cancer, while the new treatment strategies targeting their TC may represent a new dimension of cancer treatments.

SOURCE: CTCs Genet., August 25, 2021