“In January 2023, diagnosed with numerous metastases of lung cancer in my brain, I felt that I must accomplish a mission. If everything happens for a reason, my cancer, in particular, I must find out how metastatic cancer can be treated with curative intent. This is my mission now, and the reason I was ever born. In January 2023, I understood the meaning of life, of my life. I was born to write this article. In this article, I argue that monotherapy with targeted drugs, even when used in sequence, cannot cure metastatic cancer. However, preemptive combinations of targeted drugs may, in theory, cure incurable cancer. Also, I share insights on various topics, including rapamycin, an anti-aging drug that can delay but not prevent cancer, through my personal journey.”
Keywords: lung cancer, brain metastases, capmatinib, resistance, MET
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In this new study, researchers investigated the role of Osteopontin splice variants in cancer metastasis.
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Mitochondrial biogenesis, the process of increasing the size and number of mitochondria within cells, plays a crucial role in cancer metastasis. Metastasizing cells exhibit a unique metabolism that differs from the well-known Warburg effect observed in primary tumors. While primary tumors primarily rely on glycolysis for energy production, metastatic cells rely on oxidative phosphorylation and ATP generation for short-term energy needs. However, over longer time frames, mitochondrial biogenesis becomes a prominent feature in the success of metastasis.
In a new study, researchers Gulimirerouzi Fnu and Georg F. Weber from the University of Cincinnati’sJames L. Winkle College of Pharmacy investigate the connection between short-term oxidative metabolism and long-term mitochondrial biogenesis in cancer metastasis. They hypothesized that Osteopontin splice variants, specifically Osteopontin-c, stimulate an increase in mitochondrial size through the activation of specific signaling mechanisms. On December 1, 2023, their new research paper was published in Oncotarget, entitled, “Osteopontin induces mitochondrial biogenesis in deadherent cancer cells.”
“Over longer time frames, mitochondrial biogenesis becomes a pronounced feature and aids metastatic success. It has not been known whether or how these two phenomena are connected. We hypothesized that Osteopontin splice variants, which synergize to increase ATP levels in deadherent cells, also increase the mitochondrial mass via the same signaling mechanisms.”
The Role of Osteopontin Variants in Mitochondrial Biogenesis
Deadhesion, the process of detaching cancer cells from the extracellular matrix, is known to induce metabolic reprogramming and promote cancer cell survival in circulation. Osteopontin (OPN), a cytokine produced by cancer cells, has been implicated in tumor progression and the development of metastases. It mediates tumor cell survival and expansion under deadherent conditions, making it an ideal candidate for studying the mechanisms behind mitochondrial biogenesis. The authors of the research paper focused on two Osteopontin splice variants, Osteopontin-a and Osteopontin-c, and their effects on mitochondrial biogenesis.
Through their experiments with breast tumor cells, the authors found that both Osteopontin-a and Osteopontin-c contribute to mitochondrial biogenesis in deadherent cells. However, Osteopontin-c was more effective in stimulating an increase in mitochondrial size compared to Osteopontin-a. The authors also observed that the autocrine effects of Osteopontin variants are critical for the survival and anchorage-independence of disseminating malignant cells.
The Role of CD44v and SLC7A11 in Osteopontin Signaling
To further elucidate the mechanism behind Osteopontin-induced mitochondrial biogenesis, the authors investigated the receptors involved in Osteopontin signaling. They focused on CD44, a cell surface receptor known to interact with Osteopontin, and its variant CD44v. The authors found that Osteopontin-induced mitochondrial biogenesis is mediated via the binding of Osteopontin to CD44v.
Additionally, the authors discovered that the chloride-dependent cystine-glutamate transporter SLC7A11 plays a crucial role in Osteopontin signaling. The upregulation and co-ligation of SLC7A11, along with CD44v, leads to the activation of PGC-1, a known inducer of mitochondrial biogenesis. Surprisingly, the authors found that peroxide, an important intermediate in this signaling cascade, acts upstream of PGC-1 and is likely produced as a consequence of SLC7A11 recruitment and activation.
In Vivo Implications and Therapeutic Targets
To validate the relevance of their findings in clinical settings, the authors analyzed gene expression profiles in breast cancer metastases and metastases from other types of cancers. They identified the master regulator of mitochondrial biogenesis, PPARG, as well as its downstream effectors NRF1 and BACH1, to be upregulated in various metastases. These findings suggest that the Osteopontin-induced activation of PGC-1 and subsequent mitochondrial biogenesis may play a crucial role in cancer metastasis.
The authors also conducted in vivo experiments using mouse models. They observed that suppression of the biogenesis-inducing mechanisms led to a reduction in disseminated tumor mass. These findings not only confirm the functional connection between short-term oxidative metabolism and long-term mitochondrial biogenesis in cancer metastasis but also provide potential mechanisms and targets for treating cancer metastasis.
Conclusion
This study provides valuable insights into the role of Osteopontin splice variants in regulating mitochondrial biogenesis in metastatic cancer cells. The researchers demonstrated that Osteopontin-c stimulates an increase in mitochondrial size through the activation of specific signaling mechanisms involving CD44v and SLC7A11. These findings have significant implications for understanding the metabolic adaptations of metastatic cancer cells and suggest potential targets for therapeutic interventions. Further research is needed to fully elucidate the intricate signaling pathways involved in Osteopontin-induced mitochondrial biogenesis and to explore the clinical applications of these findings in cancer treatment.
“This study confirms a functional connection between the short-term oxidative metabolism and the longer-term mitochondrial biogenesis in cancer metastasis – both are induced by Osteopontin-c. The results imply possible mechanisms and targets for treating cancer metastasis.”
Click here to read the full research paper in Oncotarget.
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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.
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In a new research perspective, researchers discuss melatonin’s effects on cancer and the key importance of the timing of administration.
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In the realm of cancer research, the potential of melatonin as an anti-cancer agent has garnered significant attention. Over the past 50 years, numerous studies have been conducted to investigate the effects of melatonin on tumor growth and development in mice. These studies have provided valuable insights into the complex relationship between melatonin and carcinogenesis.
In 1973, Vladimir N. Anisimov and his coauthors made a groundbreaking discovery by demonstrating the inhibitory effect of melatonin on transplantable mammary tumors in mice. This pivotal study laid the foundation for subsequent investigations into the potential anti-cancer properties of melatonin. However, early studies encountered controversies regarding the consistency of melatonin’s effects on in vivo cancer models. The lack of consistency in these studies prompted further exploration of the factors influencing melatonin’s efficacy.
Importance of Timing in Melatonin Administration
One of the crucial findings in melatonin research is the significant impact of timing in melatonin administration. Bartsch and Bartsch demonstrated that the effects of melatonin on cancer in mice depend on the time of treatment. The administration of melatonin in the morning stimulated tumor growth, while late afternoon administration inhibited it. This observation highlighted the importance of considering animal conditions and the systemic effects of melatonin when evaluating its anti-cancer properties. These systemic effects may not be evident in cell cultures or ex vivo explants.
Murine Models for Melatonin and Cancer Studies
Murine models have played a pivotal role in elucidating the effects of melatonin on various types of cancer. These models have provided valuable insights into the potential utility of melatonin in oncology. Some of the notable murine models include mice grafted with murine tumors, chemically induced tumors, spontaneous carcinogenesis in mice, transgenic HER2/neu oncogene-bearing mice, and nude mice grafted with human prostate tumors. These models have allowed researchers to evaluate not only the effects of melatonin on cancer development but also its impact on the efficacy and side effects of anticancer therapies.
Melatonin’s Effects on Spontaneous Tumor Incidence
One intriguing finding in murine studies is the effect of melatonin on spontaneous tumor incidence. Anisimov et al. showed that lifelong treatment of mice with melatonin decreased the incidence of spontaneous tumors, particularly mammary carcinomas, but only at a low concentration of melatonin in drinking water. Interestingly, this effect was not observed at a high melatonin concentration. These findings suggest that the dose of melatonin may play a crucial role in its anti-cancer effects.
Melatonin’s Role in Potentiating Cytotoxic Therapy
Another area of interest in melatonin research is its potential to enhance the efficacy of cytotoxic therapy against tumors. Panchenko et al. demonstrated that the timing of melatonin administration relative to cytotoxic drug administration significantly influenced its potentiating effect on cytotoxic therapy in HER2/neu transgenic mice. This finding highlights the importance of optimizing the timing of melatonin administration in combination with other cancer treatments.
Melatonin’s Protective Effects on Side Effects
Beyond its direct anti-cancer effects, melatonin has shown promise in alleviating the side effects of cytotoxic drugs and radiation therapy. Several murine models have demonstrated the ability of melatonin to mitigate the side effects associated with these treatments. For example, melatonin was shown to alleviate the depression syndrome in mice treated with the alkylating agent temozolomide used in brain cancer therapy. Additionally, melatonin has been found to protect against ovarian follicle depletion caused by cisplatin, a commonly used chemotherapy drug. These findings suggest that melatonin may have a broader role in cancer treatment by reducing the adverse effects of traditional therapies.
Melatonin’s Effects on Metastasis and Epithelial-Mesenchymal Transition
Metastasis is a significant challenge in cancer treatment, and melatonin has shown promise in inhibiting metastatic spread. In nude mice grafted with human gastric cancer, melatonin was found to suppress lung metastases development by inhibiting the epithelial-to-mesenchymal transition (EMT). The inhibition of EMT by melatonin has also been observed in other murine models, highlighting its potential as an anti-metastatic agent. Given the crucial role of EMT in primary cancer and metastasis development, these findings have significant implications for oncology research.
Melatonin and Inflammation
Chronic inflammation is increasingly recognized as a contributing factor in cancer development and progression. Melatonin has been found to modulate inflammatory processes in murine models. In a murine model of low-grade inflammation, melatonin inhibited EMT), suggesting a potential role in suppressing cancer-related inflammation. While the direct anti-inflammatory effects of melatonin require further investigation, these findings shed light on the multifaceted mechanisms through which melatonin may exert its anti-cancer effects.
Clinical Applications and Promising Results
The employment of melatonin in clinical settings beyond its established fields does not require licensing, making it more readily accessible for testing novel applications in cancer treatment. Promising clinical results have already been reported, such as increased overall survival in prostate cancer patients with poor prognosis after combined hormone radiation treatment. These findings highlight the potential translational impact of murine studies and underscore the importance of continued research to fully understand the clinical implications of melatonin in cancer therapy.
Conclusion
Over the past 50 years, murine models have provided valuable insights into the relationship between melatonin and carcinogenesis. These studies have shed light on the importance of timing in melatonin administration, its effects on tumor incidence and metastasis, as well as its role in potentiating cytotoxic therapy and mitigating side effects. While the precise mechanisms underlying melatonin’s anti-cancer effects require further exploration, the promising results observed in both preclinical and clinical studies warrant continued investigation. As researchers continue to unravel the complexities of melatonin’s interactions with cancer, new opportunities for therapeutic interventions may emerge, offering hope for improved cancer treatment outcomes.
“The […] main lesson being that the systemic in vivo effects of melatonin on animals may overwhelm the in vitro effects found using tissue explants or cell cultures. In particular, the timing of melatonin administration is of crucial importance for using the drug, which is freely available over [the] counter and thus needs no licensing for its applications in oncology.”
Click here to read the full research perspective in Oncotarget.
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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.
Click here to subscribe to Oncotarget publication updates.
In a new study, researchers aimed to elucidate the role of cancer stemness in the resistance of colorectal cancer cells to targeted therapies.
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Colorectal cancer is the third most diagnosed cancer and the second leading cause of cancer-related deaths worldwide. It often starts in the colon or rectum with small, noncancerous clumps of cells called polyps, which can develop into cancer over time. Risk factors for colorectal cancer include age, family history, inflammatory bowel diseases, diet, smoking, and physical activity.
The development and progression of colorectal cancer are driven by the aberrant activation of multiple signaling pathways, such as EGFR (epidermal growth factor receptor), RAS-RAF, and PTEN-PI3K. Among these pathways, the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathways are particularly important, as they are frequently mutated in colorectal cancer. Therapeutic targeting of these pathways has shown promise in suppressing tumor growth. However, cancer cells often develop resistance to targeted therapies, leading to treatment failure and disease progression.
One of the major mechanisms of drug resistance in cancer is the gain of stemness in cancer cells under drug pressure. Cancer stem cells (CSCs) are a small subpopulation of cells within a tumor with the ability to self-renew and differentiate into various cell types that constitute the tumor. CSCs are thought to be responsible for tumor initiation, progression, and resistance to therapy. Therefore, identifying approaches to target CSCs is crucial for improving treatment outcomes in colorectal cancer patients.
In the current study, the researchers developed spheroid cultures of patient-derived BRAFmut and KRASmut tumor cells and studied the resistance mechanisms to inhibition of the MAPK pathway. The researchers found that treatment with MAPK pathway inhibitors enriched the expression of CSC markers CD166, ALDH1A3, CD133, and LGR5 and activated the PI3K/Akt pathway in cancer cells. These findings suggest that the development of drug resistance in colorectal cancer is associated with the acquisition of a stem cell-like phenotype.
To overcome drug resistance mediated by cancer stemness, the researchers examined various combination treatments to block these activities. They found that a triple combination treatment targeting BRAF, EGFR, and MEK significantly reduced stemness and the activities of oncogenic signaling pathways in colorectal cancer cells. This triple combination treatment has shown promise in clinical trials, with response rates of 21% and 32% in patients with BRAFmut colorectal cancer. The researchers demonstrated that this combination treatment effectively suppressed the growth, stemness, and activities of several oncogenic signaling pathways in cancer cells.
“Our finding supports the hypothesis that CSCs confer drug resistance and suppressing stemness is a viable approach in BRAFmut colorectal cancer.”
Conclusion
Altogether, the researchers found that inhibiting BRAF, EGFR, and MEK in combination shows promise in suppressing cancer stemness and overcoming drug resistance in colorectal cancer cells. This approach targets the underlying mechanisms of resistance, providing a potential strategy for improving treatment outcomes in patients with colorectal cancer. Further research and clinical trials are needed to validate the efficacy and safety of this triple combination therapy.
“In conclusion, this study presented a model of cyclic drug treatment and recovery of patient-derived tumor spheroids and established that single-agent MEK inhibition of colorectal cancer cells lead to adaptive resistance of cancer cells through gain of stemness. A triple combination treatment used in a clinical trial of colorectal cancer patients effectively blocked growth, stemness, and activities of several oncogenic signaling pathways in cancer cells. Our approach to identify mechanisms of drug resistance of patient-derived cancer cells to targeted therapies and develop effective treatments is promising toward cancer precision medicine.”
Click here to read the full research paper in Oncotarget.
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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.
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In a 2023 study, researchers investigated hair loss and their findings may lead to a better understanding of tissue homeostasis, initiation of cancer and the aging process.
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Hair follicles are dynamic structures that undergo cyclic phases of growth, regression and quiescence. The growth phase, known as anagen, lasts for several years, followed by a short regression phase called catagen. During catagen, most cells within the follicle undergo programmed cell death, but a small population of stem cells remains viable to replenish the follicle during the subsequent growth phase. Understanding the mechanisms involved in hair follicle regression is not only important for elucidating normal tissue homeostasis but also for studying pathological conditions such as cancer and aging.
“Here, we use a quantitative analysis of the length of hair follicles during their regression cycle.”
The Role of Apoptotic Cells in Hair Follicle Regression
In this study, researchers suggest that apoptotic cells play a crucial role in driving cell death during hair follicle regression. Intravital microscopy in live mice revealed that the elimination of epithelial cells involves supra-basal cell differentiation and basal cell apoptosis, which are influenced by the synergistic action of TGF-β (transforming growth factor) and mesenchymal-epithelial interactions. The study also demonstrated that the basal epithelial cells are not internally committed to death, and the mesenchymal dermal papilla (DP) is essential in inducing apoptosis.
While the exact mechanism leading to the propagation of apoptosis towards the regenerative stem cell population remains unclear, the researchers proposed a quantitative analysis of the length of hair follicles during their regression cycle. The data obtained from this analysis suggested a propagation mechanism driven by apoptotic cells inducing apoptosis in their neighboring cells. Interestingly, the study found that apoptosis slows down as it approaches the stem cells at the end of the follicle, indicating the presence of a pro-survival signal released by these stem cells.
“In this paper we introduced a mathematical model of the hair follicle regression cycle that postulates that the regression is initiated by the dermal papilla, but that this signal affects only the cells adjacent to it.”
Hair Follicle Regression & Stem Cell Niches
To understand the dynamics of hair follicle regression, it is essential to consider the concept of stem cell niches. Adult stem cells, along with their supporting cells, form these niches, which maintain the functionality of renewable tissues in various organs. Stem cell niches have been identified in organs such as the colon, breast, skin, hair follicles, and bone marrow. Each organ has a distinct stem cell niche architecture, which can influence the rate of aging and susceptibility to cancer.
The study by Keister et al. highlights the importance of stem cell niches in hair follicle regression. The mesenchymal DP cells, located at the bottom of the follicle, were implicated in the initiation of regression through the release of a pro-apoptotic signal, possibly associated with TGF-β. While the DP cells are necessary for the initiation of regression, they are not required for the completion of the regression phase. This suggests that other mechanisms, in addition to the DP signal, contribute to the observed apoptotic propagation.
Quantitative Analysis of Hair Follicle Regression
The team conducted a quantitative analysis of hair follicle length during catagen to gain insights into the dynamics of regression. The study measured the length of hair follicles at two time points separated by 12 hours using intravital microscopy. The data revealed that shorter hair follicles regress at a slower rate compared to longer follicles. This observation suggests that the apoptotic propagation slows down as the dying cells approach the regenerative stem cell pool.
To explain the observed data, the researchers proposed a quantitative model in which apoptotic cells release a local signal that primes neighboring cells for apoptosis. Simultaneously, the stem cells release a pro-survival signal, creating a spatial gradient. This model is consistent with the experimentally measured distribution of follicle lengths and the deceleration of hair follicle regression. The simulations of the model demonstrated that the propagation of apoptosis along the follicle becomes slower and eventually stops when it reaches the stem cells.
The Power Law Distribution of Follicle Lengths
In addition to the quantitative analysis, the researchers investigated the distribution of follicle lengths during catagen. They found that the data obtained from the experiments were consistent with a power law distribution. (Note: The power law refers to the relationship between two quantities, stating that a relative change in one leads to a relative change in the other.) While the power law distribution was observed in the model, it is important to note that the biological lengths of the follicles make it challenging to have high confidence in this distribution. However, the model generated a power law probability distribution function, providing further support for its validity.
Implications & Future Directions
This research paper presents a comprehensive understanding of the role of apoptotic cells in hair follicle regression. The proposed model, which involves the interplay between apoptotic cells and stem cells, provides insights into the dynamics of regression and the maintenance of stem cell niches. Further research is needed to validate the model and explore the potential application to other stem cell niches in different organs.
The findings of this study have implications for the understanding of tissue homeostasis, initiation of cancer and the aging process. By unraveling the mechanisms behind hair follicle regression, researchers can gain valuable insights into the regulation of cell death and renewal in various tissues. This knowledge can potentially lead to advancements in regenerative medicine and the development of targeted therapies for conditions related to abnormal cell death and tissue regeneration.
“In conclusion, hair follicle regression may be governed by cell-cell induced programmed cell death, which slows down as the stem cell compartment is approached and does not affect the stem cell compartment from which the growth phase is initiated. […]. The generalization of the model to different geometries and topologies of different stem cell niches, as well as to the details of their stem cell renewal kinetics can address problems related [to] disease states like cancer and aging.”
Click here to read the full research paper in Oncotarget.
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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.
Click here to subscribe to Oncotarget publication updates.
In this editorial, researchers delve into the immunotherapeutic challenges posed by the tumor microenvironment and liver metastasis in pancreatic cancer.
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Pancreatic ductal adenocarcinoma (PDA), a common type of pancreatic cancer, has proven to be largely resistant to immunotherapy, a treatment that uses the body’s immune system to fight cancer. Despite numerous successful pre-clinical trials using sophisticated PDA mouse models, clinical trials have failed to show a significant improvement in survival.
Tumor Microenvironment and Liver Metastasis: Challenges in Pancreatic Cancer
The authors attribute PDA immunotherapy resistance to the unique characteristics of the tumor microenvironment (TME). The TME is often hypoxic and fibrotic, making it inaccessible to immune cells. Furthermore, the immune cells that do infiltrate the TME often have tolerogenic features, meaning they are more likely to tolerate the presence of cancer cells rather than attack them.
PDA most commonly metastasizes to the liver, an organ known for its immune tolerance. The liver is home to a diverse array of innate immune populations, including NK cells, Kupfer cells, NKT cells, and double negative T cells. Despite this, the liver is the most common location for metastasis from gastrointestinal cancers.
“It is an unfortunate fact that all failed clinical trials assessing immunotherapeutic efficacy were conducted in metastatic PDA, whereas basic preclinical investigations are usually performed in primary PDA using genetically engineered mouse models. We postulated that this dichotomy may explain the gap between preclinical promise and ultimate clinical failure.”
Divergent Responses to Immunotherapy: Primary vs. Metastatic
“The potentially divergent responses to immunotherapy in the respective environments of primary versus metastatic PDA within the same host has not been well-studied.”
The authors highlight the lack of research into the potentially divergent responses to immunotherapy in primary versus metastatic PDA. They argue that this gap in knowledge may explain the discrepancy between the promising results of pre-clinical trials and the disappointing outcomes of clinical trials.
In their research, they discovered that the TMEs of primary PDA and liver metastases differ significantly, and this difference plays a critical role in the site-specific response to immunotherapy. They found that liver metastases are uniquely resistant to immunotherapies, in stark contrast to the immunotherapeutic responsiveness of primary PDA.
“We discovered that the respective TMEs of primary PDA and liver metastases differ markedly and this fact plays a critical role in dictating site-specific PDA response to immunotherapy [6].”
The Role of B Cells
The researchers identified B cells as a key player in this differential response. They found that B cells constituted approximately 25% of the tumor-infiltrating lymphocytes in metastatic PDA liver deposits, compared to approximately 10% in primary PDA. They also discovered a novel population of CD24+CD44–CD40– B cells in the metastatic liver, which is recruited to the metastatic milieu by Muc1hiIL18hi tumor cells.
“[…] by targeting B cells or blocking CD200/BTLA, we demonstrated enhanced macrophage and T-cell immunogenicity, which enabled immunotherapeutic efficacy of liver metastases.”
However, the authors note that primary PDA sites lack this b-cell population. Instead, they are characterized by macrophages and effector T cells that have a higher ability to provoke an immune response. This makes their immunotherapeutic responsiveness far more robust than metastatic liver PDA.
Conclusion
This research underscores the importance of understanding the immune basis of differential responses to immunotherapy in primary versus metastatic pancreatic cancer. It highlights the need for further research into the role of the TME and immune cells like B cells in the response to immunotherapy. Such insights could pave the way for more effective treatments for this challenging disease.
“[…] our data suggest that models of primary PDA are poor surrogates for evaluating immunity or treatment response in advanced disease.”
Click here to read the full editorial paper in Oncotarget.
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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.
Click here to subscribe to Oncotarget publication updates.
In this editorial, researchers from Japan discuss their recent study investigating the role of p53 in preventing the development of extrahepatic biliary cancer.
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Extrahepatic biliary cancer is a specific type of biliary cancer that occurs outside the liver. It is considered rare, quite serious and often symptomless until later stages. The average age at diagnosis is 72. Extrahepatic biliary cancer typically involves the bile ducts, which carry bile from the liver and gallbladder to the small intestine. It can also involve the gallbladder, which plays a role in the digestion of fats by storing, concentrating and releasing bile as needed.
One of the main genetic factors that contribute to biliary cancer is the mutation of Kras, a gene that regulates cell growth and division. Mutated Kras can cause cells to grow uncontrollably and form tumors. Another important genetic factor is the mutation of p53, a gene that normally acts as a guardian of the genome and triggers cell death or repair when DNA damage occurs. Mutated p53 can impair this function and allow cells to survive and accumulate more mutations.
“[…] the exact role of p53 in the development of extrahepatic biliary cancer remains elusive.”
The authors of the editorial discuss their 2022 study using a mouse model to investigate how Kras and p53 mutations interact in the development of extrahepatic biliary cancer. They found that mice with Kras activation and p53 inactivation developed lesions resembling human biliary neoplasms in the bile duct and gallbladder. These lesions are considered to be precursors of invasive biliary cancer.
“In this study, we found that simultaneous activation of Kras and inactivation of p53 induces biliary neoplasms that resemble human biliary intraepithelial neoplasia in the extrahepatic bile duct and intracholecystic papillary tubular neoplasm in the gall bladder in mice.”
However, they also found that p53 inactivation was not enough for the progression of these lesions into invasive cancer in the presence of oncogenic Kras within the observation period. This was also true when they added another genetic alteration, namely the activation of the Wnt signaling pathway, which is known to promote tumorigenesis in various cancers.
Therefore, they concluded that p53 has a protective role against the formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras. They suggested that additional genetic or environmental factors may be required for the malignant transformation of these lesions into invasive cancer.
“In conclusion, p53 protects against formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras in mice, however, inactivation of p53 is not sufficient for the progression into invasive cancer in the extrahepatic biliary system.”
Click here to read the full editorial paper in Oncotarget.
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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.
Click here to subscribe to Oncotarget publication updates.
In a new editorial paper, researchers highlight the role of GLS2 in regulating ferroptosis in hepatocellular carcinoma.
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Hepatocellular carcinoma (HCC) is the most common type of liver cancer. It is particularly challenging to treat because HCC is often diagnosed in late stage and resistant to chemotherapy and radiation. However, advancements in targeted therapies and immunotherapies have opened new avenues for the treatment of this aggressive disease.
In a new editorial paper, researchers Sawako Suzuki, Divya Venkatesh, Tomoaki Tanaka, and Carol Prives from Columbia University highlight the role of a metabolic enzyme known as glutamine synthase 2 (GLS2) in regulating ferroptosis in HCC. Ferroptosis is a form of cell death that involves iron-dependent accumulation of lipid peroxides. On October 19, 2023, their editorial was published in Oncotarget, entitled, “GLS2 shapes ferroptosis in hepatocellular carcinoma.”
GLS2 Promotes Ferroptosis in HCC
GLS2 is a key enzyme that catalyzes the conversion of glutamine to glutamate, a precursor of alpha-ketoglutarate (αKG), a molecule that participates in several metabolic pathways, such as the tricarboxylic acid (TCA) cycle, redox homeostasis and lipid and amino acid metabolism. GLS2 is also a transcriptional target of the tumor suppressor protein p53, which regulates its expression in response to cellular stress.
In this editorial, the researchers summarize findings from their recent study, which demonstrated that GLS2 is a bona fide tumor suppressor and a regulator of ferroptosis in HCC using mouse models and human cancer cells. The team showed that GLS2 deficiency leads to increased HCC tumorigenesis and resistance to ferroptosis, while GLS2 overexpression reduces tumor growth and sensitizes cancer cells to ferroptosis.
The mechanism by which GLS2 promotes ferroptosis involves its catalytic activity, which facilitates the production of αKG from glutamate. αKG then enhances lipid reactive oxygen species (ROS) generation by inhibiting the activity of glutathione peroxidase 4 (GPX4), an enzyme that protects cells from lipid peroxidation. Thus, GLS2 acts as a metabolic switch that favors ferroptosis by increasing lipid ROS levels.
“Our work has now provided evidence that GLS2 is mainly localized in mitochondria and induces ferroptosis through α-ketoglutarate (αKG), and this occurs specifically under conditions where the levels of GSH [glutathione] or of glutathione peroxidase 4 (GPX4) are suppressed by ferroptosis inducers [7].”
Conclusions
The authors also provided evidence that GLS2-mediated regulation of ferroptosis has clinical relevance for human HCC. They found that GLS2 expression is frequently downregulated in human HCC samples and correlates with poor prognosis. Moreover, they showed that GLS2 expression is associated with sensitivity to erastin, a ferroptosis-inducing agent, in human HCC cell lines.
These results suggest that GLS2 is a potential therapeutic target for HCC and that its modulation could enhance the efficacy of ferroptosis-based therapies. The editorial paper concludes by discussing the challenges and opportunities for further research on the role of GLS2 and ferroptosis in liver disease.
“If indeed GLS2 can promote chemically-induced ferroptosis irrespective of the tissue type, then the drug regimen will need to be tailored such that the liver tissues adjacent to HCC are protected. Taking these concerns into consideration, we hope that our findings will inform future decisions regarding treatment of liver disease.”
Click here to read the full editorial paper in Oncotarget.
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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.
Click here to subscribe to Oncotarget publication updates.
In this new study, researchers aimed to determine the genetic predisposition to early breast cancer in women from Kazakhstan.
Breast cancer (BC) is one of the most common and deadly cancers worldwide, affecting millions of women every year. However, not all women share the same risk of developing breast cancer. There are many factors that influence this disease, including age, lifestyle, family history, and genetic makeup.
One of the most important aspects of breast cancer research is to identify the genetic factors that predispose some women to develop breast cancer at an early age, especially in different ethnic groups that may have unique genetic variants. This can help to improve the prevention, diagnosis and treatment of breast cancer, as well as to reduce the health disparities among different populations.
“Our study may reveal previously uncharacterized population-specific variants that may increase the risk of BC in the Kazakh population.”
The Study
The researchers enrolled 224 unrelated Kazakh women diagnosed with early onset breast cancer. All patients were treated at the Kazakh Institute of Oncology and Radiology from August 2017 to October 2019. Cohort characteristics reported that the median age of the women was 34.6 years old (ranging between 19 and 40 years), 15.6% were diagnosed under the age of 30 and 13.8% had breast cancer within their family history. The researchers utilized next-generation sequencing (NGS) to perform a comprehensive analysis of germline mutations and gene expression profiles using the MiSeq platform. They used a targeted panel of 94 cancer-associated genes, including a vast number of genes implicated in hereditary cancer syndromes and overall breast cancer predisposition.
“To our knowledge, this is the first study using NGS technology to study the genetic predisposition to early-onset BC women from Kazakhstan and assess their impact on the patients’ clinical outcomes.”
The NGS-based multigene panel testing allowed the researchers to identify recurrent, possible founder and novel PVs in Kazakh women with early-onset BC that were undetected in earlier studies. Among 57 patients (25.4%), 38 unique pathogenic variants (PVs) were identified in 13 different cancer-predisposing genes. Notably, 12 of the 38 PVs were recurrent, including specific variants in BRCA1 and BRCA2 genes, which may represent founder mutations in this population. BRCA1 carriers had a significantly higher likelihood of developing triple-negative breast cancer and having a family history of breast cancer compared to non-carriers. Six of the 38 variants were novel.
“We demonstrated the remarkable efficacy of an NGS-based panel to identify rare germline variants in early onset BC patients. These findings could contribute to the development of population-specific multigene panels for more rapid and cost-effective testing.”
Conclusions
The study provides valuable insights into the genetic predisposition of early breast cancer in women of Kazakh ethnicity. It also highlights the value of next generation sequencing technology and the importance of studying different ethnic groups to understand the diversity and complexity of breast cancer genetics. The authors suggest that broadening the scope of genetic testing for hereditary breast cancer from only BRCA genes to testing multiple genes at once could lead to better results. However, further studies are needed to validate the clinical utility of the panels used in this study. Nonetheless, these findings may aid in developing personalized risk assessment and management strategies for Kazakh women with early-onset breast cancer, as well as to inform future clinical trials and treatments.
“With this in mind, we will focus in the future on segregation analyses of family members and functional analyses to evaluate the inheritance pattern and pathogenicity of the identified recurrent and novel BC variants. Retrospective analyses of their possible association with progression-free, metastasis-free, and overall survival are also an exciting direction for future research. No less interesting would be the study of these variants regarding the chemosensitivity and efficacy of specific targeted therapies for their carriers.”
Click here to read the full research paper in Oncotarget.
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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.
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In a recent editorial, researchers discuss targeting fatty acid binding proteins to fight multiple myeloma.
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Multiple myeloma (MM) is a type of blood cancer that affects plasma cells, which are responsible for producing antibodies. MM is characterized by the accumulation of abnormal plasma cells in the bone marrow, leading to bone damage, kidney failure, anemia, and increased susceptibility to infections. MM is a heterogeneous disease with different subtypes and genetic mutations that affect the prognosis and response to treatment. Therefore, there is a need for new biomarkers and therapeutic targets that can improve the outcomes of MM patients.
One of the potential targets that has recently emerged is the fatty acid binding protein (FABP) family. FABPs are proteins that bind and transport fatty acids, which are essential for energy production, cell signaling and membrane synthesis. FABPs are expressed in various tissues and organs, and have different roles depending on their location and type. There are nine members of the FABP family, but FABP5 seems to be the most relevant for MM.
“The FABPs hold promise as new therapeutic targets in multiple myeloma (MM), as described by our laboratory, and supported by in silico analyses [2] and other data [3, 4].”
Editorial Summary
The authors found that FABP5 expression is higher in MM cells than in normal plasma cells, and that high FABP5 levels are associated with worse survival and progression in MM patients. They also show that FABP inhibitors can reduce MM cell growth, survival and proliferation by affecting various pathways and processes, such as:
The unfolded protein response and ER stress response, which are activated by the high protein production in MM cells
The reactive oxygen species (ROS) generation, which can cause oxidative damage and apoptosis
The MYC oncogene expression and activity, which is essential for MM cell survival and proliferation
The mitochondrial function and metabolism, which are altered in MM cells to favor fatty acid oxidation
The DNA methylation patterns, which can affect gene expression and epigenetic regulation
The immune cell infiltration and cytokine production in the bone marrow microenvironment, which can modulate the tumor-host interactions
The researchers also highlighted findings from other studies that support the importance of FABPs in MM. For example, Jia et al. found that FABP5 expression correlates with immune cell changes in the MM microenvironment. Liang et al. found that FABP4 expression is increased in MM patients and that FABP4 knockout or inhibition can improve survival and reduce tumor burden in mice models.
“We reported studies showing either decreased tumor burden or no effect of FABP inhibition in vivo, and thus further optimization of in vivo targeting of FABPs, FABP inhibitor design, or overcoming FABP inhibitor resistance in the bone marrow is still required before translation to the clinic can materialize [1].”
Conclusion
The authors conclude that FABPs are promising prognostic markers and therapeutic targets in MM, and that further research is needed to elucidate their mechanisms of action and to develop specific inhibitors. They also suggest that targeting both tumor cell-derived and microenvironment-derived FABPs may be more effective than targeting either one alone.
This editorial provides a concise overview of the current state of knowledge on FABPs in MM, and highlights the potential benefits of targeting them for MM treatment. It also raises some interesting questions for future research, such as:
How do FABPs interact with other metabolic pathways and regulators in MM cells?
How do FABPs affect the bone remodeling process and osteolytic lesions in MM?
How do FABPs influence the drug resistance and relapse in MM?
How do different types of FABPs cooperate or compete with each other in MM?
How can FABP inhibitors be combined with other therapies for optimal efficacy and safety?
“Still, we are hopeful that by targeting FABPs, or following the science to other related pathways, it will be possible to revolutionize the therapy regimes currently used for MM patients.”
Click here to read the full editorial in Oncotarget.
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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.
Click here to subscribe to Oncotarget publication updates.
