Tagged: Liver Cancer

Immunotherapy Response in Primary vs Metastatic Pancreatic Cancer

November 16, 2023

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.

In a recent editorial, researchers Brian Diskin, Sarah Schwartz and George Miller from Trinity Health of New England shed light on the complex interplay between the immune system and pancreatic cancer. Their paper was published in Oncotarget on April 24, 2023, and entitled, “The critical immune basis for differential responses to immunotherapy in primary versus metastatic pancreatic cancer.”

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.

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How a Metabolic Enzyme Can Trigger Cell Death in Liver Cancer Cells

October 19, 2023

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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Unconventional Protein Secretion (UPS) in Cancer

March 16, 2023

Researchers from The Jikei University School of Medicine published a recent editorial perspective in Oncotarget, entitled, “Leakage? or Secretion? unconventional protein secretion in cancer.”

unconventional protein secretion in cancer — 3D rendering of structure/anatomy of human cell with organelles, nucleus, membrane, mitochondria, Golgi apparatus

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Conventional protein secretion is fairly well understood in this day and age. Proteins that are secreted through the classical, secretory vesicle-related pathway contain a signal peptide that guides them to the endoplasmic reticulum (ER), where they are further processed and transported to the Golgi apparatus. From there, the Golgi apparatus modifies, sorts and packages proteins for transport to their final destinations within the cell or for secretion outside of the cell.

However, in recent years, it has become clear that not all secreted proteins follow this conventional pathway. Instead, some proteins are secreted through unconventional pathways that do not require a signal peptide or the involvement of the ER or Golgi apparatus. In a recent editorial perspective published in Oncotarget on February 20, 2023, “Leakage? or Secretion? unconventional protein secretion in cancer,” researchers Kohji Yamada and Kiyotsugu Yoshida from The Jikei University School of Medicine in Tokyo, Japan, discuss unconventional protein secretion (UPS) and its significance in the progression of cancer.

“In contrast, the secretion of proteins that do not code for signal peptides may occur via two or more mechanisms, often collectively referred to as unconventional protein secretion (UPS).”

UPS in Cancer

The mechanism of action of UPS in cancer cells is still unclear, however, UPS may be carried out through multiple mechanisms. One such mechanism is the lysosome-mediated secretion pathway, in which proteins are secreted through lysosome organelles that break down and recycle cellular waste. Another mechanism is the exosome-mediated secretion pathway, in which proteins are packaged into small vesicles called exosomes and released from the cell.

In their editorial perspective, Yamada and Yoshida focus on the unconventional secretion of proteins in cancer cells. They note that these unconventional pathways have been implicated in the progression of various types of cancer, especially in liver cancers. The authors quickly began to discuss the question in the title of their paper: leakage or secretion? Since cancer cells are often surviving in harsh external environments, they tend to undergo damage to their cellular membranes. This makes it difficult to identify whether the proteins found in the extracellular environment have been leaked or secreted from the cell.

“Particularly, in liver cancer, cytosolic proteins are secreted actively, but not just leaked. In our experiments with liver cancer cell lines, we demonstrated that proliferating cells under normal culture conditions release importin α1 and PKCδ [2, 3].”

The researchers then delve into the different proteins secreted through UPS and their role in cancer. They note that cancer cells often secrete proteins that promote tumor growth and metastasis through these unconventional pathways. For example, the lysosome-mediated secretion of the protein cathepsin B has been shown to promote cancer cell invasion and metastasis. Exosome-mediated secretion of various proteins, including growth factors and cytokines, has been linked to tumor growth and immune evasion.

Conclusion

Overall, the editorial perspective by Yamada and Yoshida provides valuable insight into the significance of unconventional protein secretion in cancer. While further research is needed in order to understand UPS, this editorial perspective highlights its potential as a therapeutic target. The authors emphasize the importance of continuing research into this area of cancer biology.

“In conclusion, we and other researchers have accumulated a series of evidences on UPS and its biological significance in cancer. However, the mechanism of action of UPS in cancer cells remains unclear. How cytosolic proteins localized to the ER via E-Syt1 migrate into vesicles for secretion or whether their secretory mechanisms involve other organelles, including the Golgi apparatus, autophagosomes, or lysosomes, remains unclear. In the future, if the route of UPS that is centered on E-Syt1 is elucidated, this will presumably lead to not only a basic understanding of liver cancer but also to the development of diagnostic and therapeutic strategies.”

Click here to read the full editorial perspective published in Oncotarget.

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Plasma Growth Hormone in HCC: A Biomarker of Response to Atezo/Bev?

December 8, 2022

In a new study, researchers investigated the plasma growth hormone as a potential biomarker of response to atezolizumab and bevacizumab in advanced hepatocellular carcinoma patients.

Plasma Growth Hormone in HCC: A Biomarker of Response to Atezo/Bev?

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Hepatocellular carcinoma (HCC) is a highly aggressive cancer of the liver with a very poor prognosis; many patients pass away within a year of diagnosis. Currently, there is no effective screening method for HCC and thus, 80% of patients are diagnosed at advanced stages. This makes treatment difficult and often unsuccessful. As a result, new treatments for HCC are constantly being explored.

Atezolizumab and bevacizumab are two standard therapies used to treat unresectable, advanced HCC. However, researchers Yehia I. Mohamed, Dan G. Duda, Muhammad O. Awiwi, Sunyoung S. Lee, Lina Altameemi, Lianchun Xiao, Jeffrey S. Morris, Robert A. Wolff, Khaled M. Elsayes, Rikita I. Hatia, Aliya Qayyum, Shadi M. Chamseddine, Asif Rashid, James C. Yao, Armeen Mahvash, Manal M. Hassan, Hesham M. Amin, and Ahmed Omar Kaseb from MD Anderson Cancer Center, Massachusetts General Hospital, Harvard Medical School, Michigan State University, and University of Pennsylvania Perelman School of Medicine noticed a significant gap in research on biomarkers of response in advanced HCC patients treated with atezolizumab plus bevacizumab. The team conducted a new study aimed at beginning to close this gap. On December 6, 2022, their research paper was published in Oncotarget’s Volume 13, entitled, “Plasma growth hormone is a potential biomarker of response to atezolizumab and bevacizumab in advanced hepatocellular carcinoma patients.”

“This study investigated the biomarker value of plasma growth hormone (GH) level as a potential biomarker to predict outcome in unresectable HCC patients treated with current standard therapy, atezolizumab plus bevacizumab (Atezo/Bev).”

The Study

Plasma growth hormone (GH) is a potential biomarker that had not previously been evaluated in relation to this treatment regimen in HCC before. In this study, the researchers included 37 patients with advanced HCC. The patients received atezolizumab plus bevacizumab at the MD Anderson Cancer Center between June 2018 and November 2021. The median age of the patients was 67 years old, and the vast majority were male (83.8%).

The team measured plasma GH levels, progression-free survival (PFS) and overall survival (OS). Plasma GH levels were measured by ELISA and used to stratify the HCC patients into GH-high and GH-low groups. The Kaplan-Meier method was used to calculate median OS and PFS. The Log-rank test was used to compare survival outcomes between GH-high and -low groups.

“To the best of our knowledge, this is the first study to assess clinical prognostic value of plasma GH level in patients who have received atezolizumab plus bevacizumab in clinical setting.”

The results of the study showed that plasma GH levels significantly correlated with OS. At the time of the analysis, the one-year survival rate was 70% among GH-low patients and 33% among GH-high patients. OS was significantly superior in GH-low compared to GH-high patients. PFS showed a non-significant trend in favor of GH-low patients compared to the GH-high group.

Conclusion

“Despite the small data size, plasma GH levels were strongly predictive of the disease outcome in patients treated with Atezo/Bev.”

The study concluded that plasma GH levels may be a promising biomarker for predicting response to atezolizumab plus bevacizumab in advanced HCC patients. Further, plasma GH levels may be used to stratify advanced HCC patients into high- and low-risk groups. The researchers recommend further research in larger scale and different populations to validate the findings and explore plasma GH levels as a potential biomarker of response to this treatment regimen in HCC.

“In conclusion, our study demonstrate[s] that plasma GH represents a candidate biomarker for predicting treatment outcomes in patients with advanced HCC treated with Atezo/Bev. Future studies in larger randomized clinical trial and with a more diverse ethnic, race, and gender background are warranted to further validate these findings.”

Click here to read the full research paper published by Oncotarget.

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Trending with Impact: Composite Score May Further Classify HCC

May 7, 2021

In this trending study, the association between IGF/CTP composite scores, overall survival, and progression-free survival of hepatocellular carcinoma patients treated with sorafenib was investigated.

Human liver tissue under the microscope view.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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Sorafenib was the first systemic therapy approved to treat Child-Turcotte-Pugh (CTP) class A patients with advanced hepatocellular carcinoma (HCC). However, there are no biomarkers known to predict survival, treatment outcomes, or to guide this HCC systemic therapy. The insulin-like growth factor 1 Child-Turcotte-Pugh (IGF-1/CTP) composite score has emerged as a hepatic reserve assessment tool—and potential prognostic biomarker.

“Accurate assessment of the functional hepatic reserve is important to the prognostic and treatment prediction for patients with liver disease [1, 2].”

Researchers from the University of Texas MD Anderson Cancer Center, Massachusetts General Hospital, and Harvard Medical School conducted a study to assess the association of the IGF/CTP score with overall survival (OS) and progression-free survival (PFS) of HCC patients treated with sorafenib. Their paper was published in Oncotarget’s Volume 12, Issue 8 and entitled, “Insulin-like growth factor 1/Child-Turcotte-Pugh composite score as a predictor of treatment outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib.”

The Study

The majority of circulating insulin–like growth factor (IGF) is synthesized and secreted by the liver, and levels of IGF dramatically decrease in chronic liver disease and HCC. IGF can be a helpful tool to determine the prognosis of patients with advanced HCC while undergoing treatment with sorafenib. Researchers also use the Child-Turcotte-Pugh (CTP) qualitative scoring system to assess severity of liver cirrhosis, hepatic reserve, guide treatment decisions, and to stratify patients with HCC into three groups (A, B, and C). CTP class A has a better prognosis compared to classes B and C.

“Assessing liver reserve in HCC is of a great value as a tool for stratification of patients in clinical trials as well as to predict HCC outcome and guide therapy decisions in routine practice [28].”

In the researchers’ prospective study, 171 patients with HCC from the University of Texas MD Anderson Cancer Center were screened and included in this study. Of the patients, 116 were classified in CTP group A. Patient IGF/CTP scores were calculated and the researchers used the Kaplan-Meier method and log-rank test to estimate and compare the time-to-event outcomes between patient subgroups. Based on CTP and the IGF/CTP scores, researchers reclassified group A patients into AA and AB risk groups, which differed significantly in terms of OS and PFS. The researchers followed up with all patients in the study until disease progression or death. Unfortunately, during the follow-up period, 100 patients passed away.

“After IGF/CTP scoring, 87 of 116 CTP class A patients were reclassified as IGF/CTP-A (AA) and 29 patients were reclassified as IGF/CTP-B (AB) (Supplementary Table 1).”

Results & Conclusion

“Our study is the first prospective validation of the IGF/CTP scoring system association with the outcomes among patients with HCC treated with sorafenib.”

This study supported the researchers’ hypothesis that the IGF/CTP score is capable of further distinguishing and refining CTP class A patients. However, for CTP class A patients, due to limited power of the study, researchers were unable to meet the threshold for statistical significance for the OS and PFS durations of the reclassified groups AA and AB.

“Although our study was not powered to determine the predictive value of the IGF/CTP score in regard to median OS and PFS durations in CTP class A patients treated with sorafenib, our subset analyses of OS and PFS at different timepoints were statistically significant and, if independently validated, could change the standard approach to assessing hepatic reserve in patients with HCC.”

Click here to read the full scientific study, published by Oncotarget.

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