May 22, 2022

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What are Cancer Metastasis Mechanisms and Treatment Strategies?



 

What are Cancer Metastasis Mechanisms and Treatment Strategies?

Nature Cancer Summary:Cancer Metastasis Mechanisms and Treatment Strategies.



Cancer metastasis is the main cause of cancer-related death. Although the development of cancer drugs has been close to a hundred years, the 5-year survival rate of metastatic cancer patients, especially those with distant metastases , is still very low (Figure 1) [1] , and very few There are effective treatment strategies that specifically target metastasis.

This article will mainly introduce the process and types of cancer metastasis, the limitations of current treatment methods and future treatment prospects [ 3] .

 

The process of cancer metastasis can be roughly divided into the following steps: in situ tumor growth, angiogenesis, epithelial-mesenchymal transition ( EMT) , invasion, intravasation, survival in the blood circulation, extravasation, dormancy or metastatic tumor growth (Figure 2). [ 2] .

At present, only late-stage secondary tumors can be detected clinically. At this time, multiple metastases have often occurred, and the situation is not optimistic. It is difficult to detect cancer cells or micrometastases in the dormant stage, which further aggravates the treatment costs. difficulty.

 

Nature Cancer In-depth Summary | Cancer Metastasis Mechanisms and Treatment StrategiesFigure 2. The process of cancer metastasis

 

Tumor staging is based on the size of the primary tumor, the depth and extent of invasion, and whether adjacent organs are involved, the presence or absence of local and distant lymph node metastasis, and the presence or absence of hematogenous or other distant metastases. , which are mainly divided into three categories: T, N, and M (Figure 3). Once distant metastasis occurs, it is considered advanced cancer. Common sites of metastases are bone, liver, and lung.

 

Nature Cancer In-depth Summary | Cancer Metastasis Mechanisms and Treatment Strategies
Figure 3. Tumor staging

 

At present, the main treatment options for cancer metastasis include: inhibiting angiogenesis, preventing epithelial-mesenchymal transition, and finding actionable metastasis suppressors .

The following is the preclinical and clinical research progress of some drugs for the treatment of metastasis (Figure 4).

Denosumab is a monoclonal antibody against RANKL, which inhibits the bone metastasis of cancer cells by inhibiting the activation of osteoclasts.

It was approved in 2018 for the prevention of multiple Bone-Related Events (SRES) in Patients with Myeloma and Bone Metastases; bevacizumab is a monoclonal antibody against VEGF that inhibits tumor angiogenesis and is approved for the treatment of colon, lung, brain, kidney and cervical cancer in adults. However, these drugs are found to be highly toxic during use, and the quality of life of patients has not been significantly improved.

At the same time, drug resistance occurs. Therefore, it is urgent to develop new small-molecule drugs and biological drugs for the treatment of metastasis.

 

Nature Cancer In-depth Summary | Cancer Metastasis Mechanisms and Treatment StrategiesFigure 4. Preclinical and clinical research progress of some drugs for the treatment of metastasis

 

Dedifferentiation and phenotypic plasticity have been a focus in the study of cancer metastasis, as earlier studies have shown that less differentiated cancers have a higher risk of metastasis and acquired resistance , in which the transition of cells to a stem cell state is acquired resistance The essential.

Epigenetic modifications produced by DNA methyltransferases (DNMT1-DNMT4), histone methyltransferases (EZH2), and histone deacetylases (HDACs) inhibit tumor suppressors while promoting dedifferentiation to enhance plasticity and resistance.

Metastatic capacity and acquired drug resistance are also associated with metabolic reprogramming , which enhances the reducing capacity of tumor cells through NAD(P)H production pathways such as lipid catabolism and antioxidant pathways.

Cellular plasticity, EMT, stemness and metastasis are often driven by abnormal activity of key developmental pathways (TGF-β, Wnt, Notch and SHH).

Metastatic ability, acquired resistance, and plasticity are intrinsically linked to genetic, epigenetic, and metabolic reprogramming, and these pathways offer promising therapeutic directions for drug development (Fig. 5) [ 3] .

 

Nature Cancer In-depth Summary | Cancer Metastasis Mechanisms and Treatment StrategiesFigure 5. The relationship between epigenetics, metabolic reprogramming, signaling pathways and transfer of cellular plasticity

 

Notch signaling is initiated by Delta-like (DLL1-DLL4) or Jagged (JAG1 and JAG2) ligands that bind to NOTCH1-NOTCH4 receptors.

This results in proteolytic cleavage and translocation of the Notch intracellular domain (NICD) to the nucleus, which then induces transcriptional activation.

Notch signaling plays a key role in development and its dysregulation is central to cancer plasticity.

SHH signaling is associated with stemness and metastasis, stromal activation and acquired drug resistance during tumorigenesis, and the central transcription factors of SHH signaling are GLI1 and GLI2, which are abnormally overexpressed in bone metastatic tumor cells.

The Wnt pathway is the transduction of downstream signaling pathways stimulated by the binding of ligand protein Wnt and membrane protein receptors, and is also related to tumor metastasis.

Wnt also maintains plasticity through the expression of OCT4 to induce dedifferentiation.

At present, there are many therapeutic methods targeting Notch, SHH and Wnt pathways in clinical practice [ 4] .

 

Figure 6. Notch, SHH, Wnt signaling pathway


Driver genes that promote uncontrolled proliferation of cells and adaptive genes that allow cancer cells to survive in environments of internal and exogenous stress are two important pathways of oncogenic progression.

Analysis of patients’ cancer genomes revealed that most cancers are driven by only 2 to 8 mutations, and instead, metastasis is a discrete step in tumor evolution that may be independent of specific genetic mutations, but instead select to suppress tumorigenesis generated during tumorigenesis Stress during immunity, genotoxicity and treatment.

 

Figure 7. Common processes in primary tumors and metastatic processes

 

Given the impact of immunotherapy on tumors that were previously considered incurable, and the fact that the immune tumor microenvironment has also emerged as a key factor in regulating metastasis, harnessing the immune system to treat tumor metastasis has become a hot research topic.

Immune checkpoint blockade therapy targeting PD-1/PD-L1 and CTLA-4 has become the focus of the treatment of cancer metastasis, and second-generation immune checkpoint receptors include TIM3, LAG3, TIGIT, B7-H3, Siglec-15 and VISTA, both have shown promise as anti-metastatic agents at various stages of clinical trials.

Metastatic lesions can be immunosuppressed by activating key immune regulatory cell types including TAMs, regulatory DCs, T reg cells, etc., which prevent effector T (T eff ) cells from recognizing and destroying tumor cells. PD-1/PD-L1 inhibitors have shown potent efficacy in the treatment of patients with metastatic tumors.

For immunocold tumors , depletion of immunosuppressive cells or inhibition of various differentiation/growth pathways by antibody therapy (targeting CSF1R, MARCO, and CD25) may promote durable remission in metastatic cancer.


Figure 8. Targeting the tumor immune microenvironment to treat cancer metastasis

 

 

 

 


Conclusion

 

Cancer metastasis is a multifactorial process that relies on plasticity and stress responses as well as an immunosuppressive environment, so the strategies to treat metastatic tumors are more complex than primary tumors, and it is gratifying that some candidate targets have been validated as In addition, the combination of elimination of immunosuppressive factors and tumor-intrinsic targeting is critical to improve overall survival.

The importance of lifestyle and diagnostics in reducing cancer mortality needs to be appreciated while finding new treatments, and for those cancers that metastasize slowly, improved diagnostics will greatly improve survival.

Therefore, prevention , early diagnosis , and treatment approaches must all be fully optimized to further reduce cancer mortality.

 

 

 

 

 

 

 

 

References:
[1] Steeg, Patricia S. “Targeting metastasis.” Nature reviews. Cancer vol. 16,4 (2016): 201-18.

[2] Understanding metastasis: current paradigms and therapeutic challenges in breast cancer progression, Royal College of Surgeons in Ireland Student Medical Journal 2010; 3: 56-60

[3] Esposito M, Ganesan S, Kang Y. Emerging strategies for treating metastasis[J]. Nature Cancer, 2021, 2(3): 258-270.

[4] Takebe N. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015 Aug;12(8):445-64.

What are Cancer Metastasis Mechanisms and Treatment Strategies?

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