Carbon Chemist

Tag: Metastasis

  • Understanding how stress accelerates cancer spread

    Understanding how stress accelerates cancer spread

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    Stress is inevitable. But too much of it can be terrible for our health. Chronic stress can increase our risk for heart disease and strokes. It may also help cancer spread. How this works has remained a mystery-;a challenge for cancer care.

    Xue-Yan He, a former postdoc in Cold Spring Harbor Laboratory (CSHL) Adjunct Professor Mikala Egeblad’s lab, says, “Stress is something we cannot really avoid in cancer patients. You can imagine if you are diagnosed, you cannot stop thinking about the disease or insurance or family. So it is very important to understand how stress works on us.”

    Now, He and Egeblad may have reached a breakthrough in understanding exactly that. Working with CSHL Professor Linda Van Aelst, they discovered that stress causes certain white blood cells called neutrophils to form sticky web-like structures that make body tissues more susceptible to metastasis. The finding could point to new treatment strategies that stop cancer’s spread before it starts.

    The team arrived at their discovery by mimicking chronic stress in mice with cancer. They first removed tumors that had been growing in mice’s breasts and spreading cancer cells to their lungs. Next, they exposed the mice to stress. What He observed was shocking. 

    She saw this scary increase in metastatic lesions in these animals. It was up to a fourfold increase in metastasis.” 

    Mikala Egeblad, Adjunct Professor, CSHL

    The team found that stress hormones called glucocorticoids acted on the neutrophils. These “stressed” neutrophils formed spider-web-like structures called NETs (neutrophil extracellular traps). NETs form when neutrophils expel DNA. Normally, they can defend us against invading microorganisms. However, in cancer, NETs create a metastasis-friendly environment.

    To confirm that stress triggers NET formation, leading to increased metastasis, He performed three tests. First, she removed neutrophils from the mice using antibodies. Next, she injected a NET-destroying drug into the animals. Lastly, she used mice whose neutrophils couldn’t respond to glucocorticoids. Each test achieved similar results. “The stressed mice no longer developed more metastasis,” He says.

    Notably, the team found that chronic stress caused NET formation to modify lung tissue even in mice without cancer. “It’s almost preparing your tissue for getting cancer,” Egeblad explains.

    To Van Aelst, the implication, though startling, is clear. “Reducing stress should be a component of cancer treatment and prevention,” she says.

    The team also speculates that future drugs preventing NET formation could benefit patients whose cancer hasn’t yet metastasized. Such new treatments could slow or stop cancer’s spread, offering much-needed relief.

    Source:

     Cold Spring Harbor Laboratory

    Journal reference:

    He, X.-Y., et al. (2024). Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment. Cancer Cell. doi.org/10.1016/j.ccell.2024.01.013.

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  • Treatment modalities shape infection profiles in advanced lung cancer patients

    Treatment modalities shape infection profiles in advanced lung cancer patients

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    Pulmonary malignancy is one of the most frequent and fatal cancers in older patients. Studies have shown that lung cancer patients have a high incidence of lower respiratory tract infections. This is due to the fact that these patients usually have airway obstruction, sticky sputum that is not easy to cough up, destruction of mucosal surfaces, and treatment with radiotherapy and chemotherapy. When most patients are found to have lung cancer, they have already developed distal metastasis and lost the chance of surgery, therefore, they usually choose to be treated with radiotherapy, chemotherapy, and targeted drugs. Radiotherapy and chemotherapy may cause lung injury. Patients who develop pneumonia will delay radiotherapy, which is not conducive to the patient’s prognosis and long-term survival.

    Some patients may only require chemotherapy or may not be able to tolerate radiotherapy, while some patients may be treated with a combination of therapies. Such studies are necessary to clarify the severity and pathogenetic distribution of lower respiratory tract infections in both types of patients and to better focus on treatment. Recently, the researchers from China analyzed the clinical characteristics and pathogenic data of lower respiratory tract infections in advanced lung cancer patients with different treatment modalities, which were published in Malignancy Spectrum.

    The researchers found that compared to patients treated with just chemotherapy, those treated with combination therapy had more elevated inflammatory markers (calcitonin, blood sedimentation, and ultrasensitive C-reactive protein) and were more likely to have mixed infections after developing lower respiratory tract infections. Whereas patients treated with simple chemotherapy were more likely to have infections with viruses, those treated with combination therapy were more likely to have infections with gram-negative bacilli. Therefore, it is best to focus on the use of antibiotics and ensure the coverage of pathogens in patients with advanced lung cancer in two different treatment modalities. Since infections are more severe in combination therapy patients, it is even more important to complete drug sensitivity testing as soon as possible for early intervention.

    Source:

    Journal reference:

    Guo, R., et al. (2023). Clinical characteristics and pathogenic analysis of lower respiratory tract infections in advanced lung cancer patients with different treatment modalities. Malignancy Spectrum. doi.org/10.1002/msp2.17.

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  • Epigenetic switch controls metastasis formation

    Epigenetic switch controls metastasis formation

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    Scientists from the German Cancer Research Center (DKFZ) and Heidelberg University investigated in mice how spreading tumor cells behave at the site of metastasis: Some tumor cells immediately start to form metastases. Others leave the blood vessel and may then enter a long period of dormancy. What determines which path the cancer cells take is their epigenetic status. This was also confirmed in experiments with human tumor cells. The results of the study could pave the way for novel diagnostic and therapeutic applications.

    What makes cancer so dangerous? Cancer cells that leave the primary tumor to reach distant sites of the body where they may grow into daughter tumors, called metastases. While most primary tumors can be effectively treated, metastases are the real danger. Oncologists estimate that more than 90 percent of all cancer deaths in solid tumors are due to metastases.

    Researchers have been working for decades to understand and prevent the spread of tumor cells. However, the mechanisms that enable a cancer cell to survive in a distant organ and ultimately grow into a metastasis are still largely unknown.

    To spread throughout the body, cancer cells travel through blood and lymphatic system. Scientists at the DKFZ and at Heidelberg University have now developed a method to observe the behavior of migrating cancer cells in mice immediately upon arrival in the metastatic organ – in this case the lung.

    The team led by the two first authors Moritz Jakab and Ki Hong Lee discovered that some tumor cells, once they have arrived in the metastatic organ, leave the blood vessel and enter a resting state. Other cancer cells start to divide directly within the blood vessel and grow into metastases.

    This delicate fate decision of the metastasizing tumor cells is controlled by the endothelial cells that line the inside of all blood vessels. They release factors from the Wnt signaling pathway that promote the exit of tumor cells from the blood vessel and thereby initiate latency. When the researchers switched off the Wnt factors, latency no longer occurred.

    What distinguishes latent from growing metastasizing cancer cells?

    “At this point, we asked ourselves the question: Why do some cancer cells immediately form a metastasis, while others fall into a kind of sleep?” says Moritz Jakab. The dormant and metastasizing cancer cells did not differ genetically, nor in many other molecular aspects. But the researchers were able to detect a subtle difference: The methylation of the DNA differed between the two cell types. Tumor cells, whose DNA was less methylated, responded sensitively to the Wnt factors, which resulted in extravasation from the blood vessel and subsequent latency. On the other hand, the more methylated cancer cells did not respond to the Wnt factors, remained in the blood vessel and immediately started metastatic growth.

    To test this hypothesis, the team examined the DNA methylation status of various tumor cell lines. Indeed, they found that this directly correlated with their metastatic potential.

    These results are surprising and could have far-reaching consequences for tumor diagnosis and therapy. The results of the study could, for example, help to use certain methylation patterns as biomarkers to predict for patients how high the load of dormant cancer cells is and, thus, how likely the patient is to relapse after successful treatment of the primary tumor. But first we need to study whether natural human tumors behave in the same way as the employed cell lines or experimental tumors.”


    Hellmut Augustin, Senior Author

    Moritz Jakab, Ki Hong Lee, Alexey Uvarovkii, Svetlana Ovchinnikova, Shubharda L Kulkarni; Sevinc Jakab, Till Rostalski, Carleen Spegg, Simon Anders, Hellmut Augustin: Lung endothelium exploits suscepible tumour cell states to instruct metastatic latency.

    Source:

    German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

    Journal reference:

    Jakab, M., et al. (2024). Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency. Nature Cancer. doi.org/10.1038/s43018-023-00716-7.

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  • Engrailed-1 protein promotes pancreatic cancer progression and metastasis

    Engrailed-1 protein promotes pancreatic cancer progression and metastasis

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    Pancreatic cancer is the No. 3 cause of cancer-related deaths in the United States, and only 12% of patients survive five years after being diagnosed. Severe pancreatic cancer is associated with metastasis, and it is this spread of secondary tumors that usually causes death, but little is known about the molecular mechanisms that drive metastasis.

    In a study published Dec. 18 in Advanced Science, researchers from the University of California, Davis showed that abnormal expression of the protein Engrailed-1 (EN1) promotes pancreatic cancer progression and metastasis in vitro and in mouse models. The team also found that elevated EN1 was associated with severe, metastatic pancreatic cancer in human patients, which suggests that EN1 might make a good target for pancreatic cancer therapies.

    We identified a novel epigenetic factor that can contribute to metastasis in pancreatic cancer, which is one of the most challenging cancers to treat. A better understanding of these mechanisms would allow us to identify potential targets and improve patient survival.”


    Chang-Il Hwang, assistant professor in the UC Davis Department of Microbiology and Molecular Genetics and a senior author on the paper

    Uncovering a main actor in pancreatic metastasis

    Metastasis is an important component of pancreatic cancer progression, but researchers have not been able to identify genetic mutations responsible for it. For this reason, Hwang thought that nongenetic factors, such as epigenetic changes or altered protein production, might be at play. His team previously identified several transcription factors -; proteins that control the production of other proteins -; that are elevated in pancreatic cancers that have undergone metastasis compared to primary tumors.

    One of these proteins, EN1, is essential for the survival of neurons during development and is not usually produced in adult pancreatic cells. EN1 has been shown to promote aggressive forms of breast cancer, and it is also associated with poor prognosis in other cancers, including glioblastoma and salivary gland adenoid cystic carcinoma, but its role in pancreatic cancer had not previously been described.

    The researchers tested whether inhibiting EN1 or ramping up its expression impacted the growth and survival of pancreatic cancer “organoids” -; three-dimensional clumps of lab-grown tissue. They found that, without EN1, pancreatic cancer cells were less likely to survive and divide, but adding extra EN1 increased the tumors’ survival. Furthermore, when the researchers genetically modified mouse pancreatic cancer cell lines so that they produced more EN1 than usual, the cells showed increased rates of cell invasion and migration, key features of metastasis.

    “It’s very clear that EN1 is a really important factor behind the aggressiveness of pancreatic cancer,” said first author Jihao (Reno) Xu, a doctoral candidate in the Biochemistry, Molecular, Cellular and Development Biology graduate group. “When we take the tumor cells and make them overexpress EN1, they become more metastatic and aggressive, and when we knock it down, they become less metastatic.”

    By analyzing publicly available patient databases, the researchers also showed that EN1 is important for prognosis in human pancreatic cancer. They found that EN1 levels were elevated in a subset of patients with advanced pancreatic cancer, and that patients with elevated EN1 tended to have worse prognoses.

    “Patients with high levels of EN1 have shorter survival times, which suggests that it is contributing to the aggressiveness of pancreatic cancer,” said Hwang.

    Now, Hwang, Xu and their colleagues are working on ways to translate their findings into the clinic by testing different ways to target EN1. They also plan to continue investigating other nongenetic factors that might contribute to pancreatic cancer progression.

    “Ultimately, we want to identify new therapeutic strategies to tackle this disease,” Xu said.

    Additional authors on the paper are: at UC Davis, EunJung Lee, Keely Y. Ji, Omar W. Younis and Alexander D. Borowsky; Jae-Seok Roe, Yonsei University; Claudia Tonelli, Tim D.D. Somerville, Melissa Yao, Joseph P. Milazzo, Herve Tiriac, Youngkyu Park, Christopher R. Vakoc and David A. Tuveson, Cold Spring Harbor Laboratory; Ania M. Kolarzyk and Esak Lee, Cornell University; Jean L. Grem, Audrey J. Lazenby, James A. Grunkemeyer and Michael A. Hollingsworth, University of Nebraska Medical Center.

    The work was supported by the UC Davis Comprehensive Cancer Center Pilot Grant and the National Institutes of Health.

    Source:

    University of California – Davis

    Journal reference:

    Xu, J., et al. (2023). Engrailed‐1 Promotes Pancreatic Cancer Metastasis. Advanced Science. doi.org/10.1002/advs.202308537.

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  • Researchers discover new class of compound that targets cancer stem cells

    Researchers discover new class of compound that targets cancer stem cells

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    Many cancer therapies, in addition to producing numerous side effects, fail to achieve complete tumour remission, partly due to the presence of cancer stem cells, which are difficult to eradicate. These cells can self-renew and play a key role in tumor recurrence and metastasis processes, so there is significant interest in developing therapies that target this subset of tumour cells. 

    A collaboration between chemists from the Center for Research in Biological Chemistry and Molecular Materials (CiQUS), led by Prof. JL Mascareñas, and cell biologists from the CSIC (Instituto de Investigaciones Biomédicas Sols-Morreale, IIBM CSIC-UAM, Madrid), led by Dr. Bruno Sainz, has led to the discovery of a new class of compound that targets cancer stem cells and reduces their potential to generate tumors. For some years, Prof. Mascareñas’ laboratory has been conducting basic research on certain molecules based on metal complexes that can interact very selectively with DNA. These findings have allowed Dr. Sainz’s group to conduct extensive studies with mice implanted with patients’ tumors, demonstrating a powerful antitumor effect of these complexes. The scientists have demonstrated anticancer effects in pancreatic, colorectal, and osteosarcoma tumors, with low secondary toxicity, and studies on other types of cancer are currently underway. 

    Cancer stem cells rely on mitochondrial respiration to survive and evade the immune system’s defenses, which represents a metabolic Achilles’ heel. Mechanistic studies carried out this time suggest that the new compound, called Ru1, promotes a decrease in the expression of genes necessary for this respiration, the main energy source for these cells, causing them to lose their cancerous potential. Dr. Sainz’s group has also demonstrated that combined therapies with other antitumor agents are possible, resulting in additive effects. 

    The preliminary results of the scientific work, which also includes contributions from the USC’s ACUIGEN group, have just been published in a leading cancer research journal. All these studies have been made possible thanks to the support of different entities, including the Ignicia program (Xunta de Galicia), the Spanish Association Against Cancer, or the CaixaImpulse program (“la Caixa” Foundation), and the project is currently in an advanced stage for its transfer and preclinical valorization. 

    Source:

    Center for Research in Biological Chemistry and Molecular Materials (CiQUS)

    Journal reference:

    Alcalá, S., et al. (2024). Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy. Journal of Experimental & Clinical Cancer Research. doi.org/10.1186/s13046-023-02931-7.

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