Congratulations to Dr. Andrew Aplin for receiving a federally award (National Institute of Health/National Cancer Institute) R01 grant for his project: Mutant BRAF-regulated transcription factors in melanoma progression.
Congratulations to Dr. Andrew Aplin for receiving a federally award (National Institute of Health/National Cancer Institute) R01 grant for his project: Mutant BRAF-regulated transcription factors in melanoma progression.
Until recently, researchers thought that cell division was the only way for an aggressive cancer cell to pass its traits along. New evidence is showing that cancers can become more dangerous by exporting aggressive traits to neighboring cells via exosomes. These small packages — bubbles — of membrane released into the extracellular environment hold pieces of host RNA, DNA and proteins. Now, a new study has shown that exosomes also can hold and transfer integrin molecules known to promote metastasis in several cancers. This discovery was made in a collaborative effort of the labs of Dr. Lucia Languino, Professor of Cancer Biology and Dr. Renato Iozzo, Professor of Pathology. Both are members of the Sidney Kimmel Cancer Center at Thomas Jefferson University.
Because of the role of the αvβ6 intergrin in prostate cancer, Languino, first author Carmine Fedele and colleagues investigated whether the αvβ6 integrin might be transferred between cells via exosomes. The researchers examined the exosomes released from prostate cancer cell lines known to express the αvβ6 integrin and found that the exosomes were enriched with this integrin. The research also was supported by the work of Amrita Singh, a graduate student in Languino’s lab.
The results were published in the Journal of Biological Chemistry. “This is an important addition to the research showing that tumors have novel ways of spreading aggressive traits,” says senior author Dr. Lucia Languino.
Congratulations to Andrew Aplin, PhD, for his appointment to lead Basic Science for the SKCC! Dr. Aplin has already distinguished himself as the leader of the Cancer Cell Biology and Signaling Program, and he will bring his energy and scientific expertise to all aspects of basic research here at the Sidney Kimmel Cancer Center. Please join us in congratulating him on this new expanded role.
Dr. Aplin’s research laboratory focuses on melanoma, the deadliest form of skin cancer. Since 2002, he has identified downstream targets of mutant BRAF-MEK-ERK signaling in melanoma, demonstrated the contribution of these targets to the malignant traits, and analyzed the influence of the tumor microenvironment. More recently, his lab has analyzed the determinants of response and mechanisms of resistance to BRAF inhibitors. Through his collaborations with Takami Sato and Carol Shields on the Jefferson campus, Dr Aplin and his team are extending their studies into ocular melanoma. His laboratory also collaborates with clinicians in the Melanoma Center of Excellence at Jefferson and with melanoma researchers at the University of Pennsylvania and the Wistar Institute. Through this research, they aim to promote the bi-directional flow of new discoveries between the laboratory and the bedside.
Andrew’s expertise and accomplishments in both basic and translational research, combined with his natural leadership skills, gives us the utmost confidence in his ability to take the helm of this important position.
Dr. Renato Iozzo, MD, PHD, Professor of Pathology & Cell Biology, Biochemistry & Molecular Biology and Kimmel Cancer Center member, and his group recently published results in the Proceedings of the National Academy of Science (PNAS) which show decorin functions as a tumor suppressor/anti-angiogenesis factor, in part, by inducing the autophagy of endothelial cells. The publication details are below:
Buraschi, S., Neill, T., Goyal, A., Poluzzi,C., Smythies,J., Owens, R.T, Schaefer, L., Torres,A. and Iozzo, R.V., Decorin causes autophagy in endothelial cells via Peg3. Proc. Natl. Acad. Sci. USA 110 (28): E2582-E2591, 2013 PMID:23798385
Several researchers from Jefferson’s Kimmel Cancer Center presented abstracts at the American Association for Cancer Research Annual Meeting 2012 in Chicago. Some of those findings include:
HuR and Ovarian Cancer
Silencing HuR may be a promising therapeutic approach for the treatment of ovarian cancer, according to an abstract presented at AACR by researchers from Thomas Jefferson University, Lankenau Institute for Medical Research, the Geisinger Clinic and the Massachusetts Institute of Technology.
HuR is a RNA-binding protein that post-transcriptionally regulates genes involved in the normal cellular response to cancer-associated stressors, like DNA damage, nutrient depletion and therapeutic agents. When triggered by stress, HuR translocates from the nucleus to the cytoplasm where it potently influences translation of key tumor promoting mRNAs by mRNA stabilization and direct facilitation of translation.
Previously, it has been shown that HuR expression is a prognostic marker in ovarian cancers. Thus, researchers tested the effects of manipulating HuR expression levels on ovarian tumor growth characteristics and tested the hypothesis that silencing HuR through delivery of an HuR siRNA would be effective in suppressing the growth of ovarian tumors.
Following treatment of ovarian cancer cells in culture with an adenovirus containing the HuR coding sequence, HuR expression was increased by about 40% above control cells.
In the patient cohort, researchers also detected HuR activation (i.e., cytoplasmic HuR positivity) in twenty-four of thirty four patients (71 percent), providing evidence that the majority of patients have activated HuR.
“These data provide evidence that silencing HuR, even as a monotherapeutic strategy, may be a promising therapeutic approach for the treatment of ovarian cancer,” wrote the authors.
Authors of the paper include Janet A. Sawicki and Yu-Hung Huang, of Lankenau Institute for Medical Research, Charles J. Yeo, Agnieszka K. Witkiewicz, Jonathan R. Brody, of Thomas Jefferson University, Radhika P. Gogoi, of Geisinger Clinic, Danville, Pa., and Kevin Love and Daniel G. Anderson, of Massachusetts Institute of Technology, Cambridge, Mass.
This work was supported by the Marsha Rivkin Center for Ovarian Cancer Research.
Radiotherapy and Glioblastoma
Radiotherapy’s effect on glioblastoma (GBM) is enhanced in the presence of a heat shock protein and a P13K inhibitor, researchers from the Department of Radiation Oncology reported at AACR.
Glioblastoma tumors frequently contain mutations in the tumor suppressor gene, PTEN, leading to loss of PTEN activity, which causes overactivation of the PI3K pathway, inducing inhibition of apoptosis and radioresistance.
Heat-shock protein 90 (HSP90) is a molecular chaperone that is over-expressed in GBM and that has among its client proteins, PI3K and Akt.
It was hypothesized that dual inhibition of HSP90 and PI3K signaling would additively or synergistically radiosensitize GBM through inhibition of radiation-induced PI3K/Akt signaling, leading to enhanced apoptosis.
Confirming their theory, the researchers found that the response of glioblastoma to radiotherapy was enhanced in the presence of BKM120 and HSP990. Enhanced apoptosis also contributed to the mechanism of cell death.
Authors of the study include Phyllis Rachelle Wachsberger, Yi Liu, Barbara Andersen, and Adam P. Dicker, of the Department of Radiation Oncology at Thomas Jefferson University Hospital and Richard Y. Lawrence, of Jefferson and the Sheba Medical Center, Tel Hashomer, Israel.
This work was supported by a grant from Novartis Pharmaceuticals.
Non-Small Lung Cancer and DACH1
Researchers from the Kimmel Cancer Center at Jefferson have identified a protein relationship that may be an ideal treatment target for non-small cell lung cancer (NSCLC). They presented their findings at AACR.
DACH1, a cell fate determination factor protein, appears to be a binding partner to p53, a known tumor suppressor, which inhibits NSCLC cellular proliferation.
As cancer develops and becomes more invasive, the expression of DACH1 decreases. Clinical studies have demonstrated a reduced expression of the DACH1 in breast, prostate and endometrial cancer.
In a previous study of more than 2,000 breast cancer patients, Jefferson researchers found that a lack of DACH1 expression was associated with a poor prognosis in breast cancer patients. Patients who did express DACH1 lived an average of 40 months longer.
Genetic studies have identified several oncogenes activated in lung cancer, including K-Ras and EGFR. Given the importance of the EGFR in human lung cancer, researchers examined the role of DACH1 in lung cancer cellular growth, migration and DNA damage response.
For this study, endogenous DACH1 was reduced in human NSCLC, with expression levels of DACH1 correlating inversely with clinical stage and pathological grade.
Re-expression of DACH1 also reduced lung cancer cell colony formation and cellular migration. Cell cycle analyses demonstrated that G2/M block by ectopic expression of DACH1 occurs synergistically with p53.
Fluorescent microscopy demonstrated co-localization of DACH1 with p53, and immunoprecipitation and western blot assay showed DACH1 association with p53.
“DACH1 enhanced the cytotoxcity of cisplatin and doxorubicin, two commonly used drugs for NSCLC,” the authors write in the abstract. “Together, our studies demonstrate that p53 is a DACH1 binding partner that inhibits NSCLC cellular proliferation.”
Authors of the study include Ke Chen, Kongming Wu, Wei Zhang, Jie Zhou, Timothy Stanek, Zhiping Li, Chenguang Wang, L. Andrew Shirley, Hallgeir Rui, Steven McMahon, Richard G. Pestell, of Thomas Jefferson University, Kimmel Cancer Center and Huazhong University of Science and Technology, Wuhan, China.
Researchers at the Kimmel Cancer Center at Jefferson have demonstrated for the first time that the metabolic biomarker MCT4 directly links clinical outcomes with a new model of tumor metabolism that has patients “feeding” their cancer cells. Their findings were published online March 15 in Cell Cycle.
To validate the prognostic value of the biomarker, a research team led by Agnieszka K. Witkiewicz, M.D., Associate Professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University, and Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology and Regenerative Medicine at Jefferson, analyzed samples of patients with triple negative breast cancer, one of the most deadly of breast cancers, with fast-growing tumors that often affect younger women.
A retrospective analysis of over 180 women revealed that high levels of the biomarker MCT4, or monocarboxylate transporter 4, were strictly correlated with a loss of caveolin-1 (Cav-1), a known marker of early tumor recurrence and metastasis in several cancers, including prostate and breast.
“The whole idea is that MCT4 is a metabolic marker for a new model of tumor metabolism and that patients with this type of metabolism are feeding their cancer cells. It is lethal and resistant to current therapy,” Dr. Lisanti said. “The importance of this discovery is that MCT4, for the first time, directly links clinical outcome with tumor metabolism, allowing us to develop new more effective anti-cancer drugs.”
Analyzing the human breast cancer samples, the team found that women with high levels of stromal MCT4 and a loss of stromal Cav-1 had poorer overall survival, consistent with a higher risk for recurrence and metastasis, and treatment failure.
Applying to a Triple Threat
Today, no such markers are applied in care of triple negative breast cancer, and as a result, patients are all treated the same. Identifying patients who are at high risk of failing standard chemotherapy and poorer outcomes could help direct them sooner to clinical trials exploring new treatments, which could ultimately improve survival.
“The idea is to combine these two biomarkers, and stratify this patient population to provide better personalized cancer care,” said Dr. Witkiewicz
The findings suggest that when used in conjunction with the stromal Cav-1 biomarker, which the authors point out has been independently validated by six other groups worldwide, MCT4 can further stratify the intermediate-risk group into high and low risk.
Since MCT4 is a new druggable target, researchers also suggest that MCT4 inhibitors should be developed for treatment of aggressive breast cancers, and possibly other types. Targeting patients with an MCT4 inhibitor, or even simple antioxidants, may help treat high-risk patients, who otherwise may not respond positively to conventional treatment, the researchers suggest.
But the work stems beyond triple negative breast cancer, challenging an 85-year-old theory about cancer growth and progression.
This paper is the missing clinical proof for the paradigm shift from the “old cancer theory” to the “new cancer theory,” known as the “Reverse Warburg Effect,” said Dr. Lisanti. The new theory being that aerobic glycolysis actually takes place in tumor associated fibroblasts, and not in cancer cells, as the old theory posits.
“The results by Witkiewicz et al. have prominent conceptual and therapeutic implications,” wrote Lorenzo Galluzzi, Ph.D., Oliver Kepp, Ph.D., and Guido Kroemer, M.D., Ph.D. of the French National Institute of Health and Medical Research and Institut Gustave Roussy, in an accompanying editorial. “First, they strengthen the notion that cancer is not a cell-autonomous disease, as they unravel that alterations of the tumor stroma may constitute clinically useful biomarkers”.
“Second, they provide deep insights into a metabolic crosstalk between tumor cells and their stroma that may be targeted by a new class of anticancer agents.”
Dr. Kroemer entitled his commentary “Reverse Warburg: Straight to Cancer” to emphasize that the connective tissue cells (fibroblasts) are directly “feeding” cancer cells, giving them a clear growth and survival advantage. New personalized therapies would cut off the “fuel supply” to cancer cells, halting tumor growth and metastasis.
Heather Montie, Ph.D., a post-doctoral research fellow in the Department of Biochemistry and Molecular Biology, has received a Prostate Cancer Foundation Young Investigator Award for her work with androgen receptor (AR) acetylation and its role in castration-resistant prostate cancer.
Young Investigator awards are designed to promote long-term careers in the field of prostate cancer by providing three year grants for transformational research focused on prostate cancer treatments to improve patient outcomes. Since 2007, PCF has invested more than $20 million in Young Investigator grants.
“PCF-supported young investigators have changed the scope of prostate cancer research, advancing treatment sciences and improving the lives of patients worldwide,” said Howard Soule, PhD, chief science officer and executive vice president of PCF. “It is with great pride and appreciation that PCF can now announce our young investigator program spans across six countries and 42 research institutes.”
Prostate cancer is driven by the male hormones, androgens which mediate their activity through the androgen receptor. Unfortunately most prostate cancerous tumors progressively become resistant to the preferred treatment modality, androgen deprivation therapy. One of the mechanisms proposed to enhance the activity of androgen receptors in castration-resistant prostate cancer, even in the absence of androgens, is the addition of a small chemical group/moiety to the AR protein. This modification of AR is termed ‘acetylation’ and is proposed to convert the protein to a ‘super AR.’
However, there is currently no experimental data to show that AR acetylation directly enhances AR-dependent prostate cancer cell viability.
Dr. Montie proposes to evaluate the role of AR acetylation in the enhanced AR functional activity central to CRPC. She will study the precise mechanisms by which this modification of AR enhances its cancer-promoting activity. Dr. Montie will also validate the potential of AR acetylation as a therapeutic target for castrate-resistant prostate cancer.
A total of 15 competitive research grants have been awarded to-date in 2012, bringing the total of young investigators awarded to 89.
Each Young Investigator recipient is awarded $225,000 over a three-year period.
Dr. Montie received the 2012 John A. Moran PCF Young Investigator Award.
Visit here for more on the Young Investigator awards.
Another layer in breast cancer genetics has been peeled back.
A team of researchers at Jefferson’s Kimmel Cancer Center (KCC) led by Richard G. Pestell, M.D., PhD., FACP, Director of the KCC and Chair of the Department of Cancer Biology, have shown in a study published online Feb. 6 in the Journal of Clinical Investigation that the oncogene cyclin D1 may promote a genetic breakdown known as chromosomal instability (CIN). CIN is a known, yet poorly understood culprit in tumor progression.
The researchers used various in vitro and in vivo model systems to show that elevated levels of cyclin D1 promotes CIN and correlate with CIN in the luminal B breast cancer subtype. Cyclin D1 protein is elevated in breast, prostate, lung and gastrointestinal malignancies.
The findings suggest that shifting towards drugs targeting CIN may improve outcomes for patients diagnosed with luminal B subtype. Luminal B breast cancer has high proliferation rates and is considered a high grade malignancy.
Estrogen or progesterone receptor positive and HER2 positive cancers indicate luminal B, and about 10 percent of patients are diagnosed with it every year, though many do not respond well to treatment. The identification of CIN in luminal B provides a new therapeutic opportunity for these patients.
“Cyclin D1 has a well defined role in cell proliferation through promoting DNA replication,” says Dr. Pestell. “My team was the first to discover that cyclin D1 also has alternate functions, which include regulating gene transcription at the level of DNA. We were interested in discovering the function of DNA associated cyclin D1.”
To help answer this, the researchers, including lead author Mathew C. Casimiro, Ph.D., of the Department of Cancer Biology at Thomas Jefferson University, first needed to directly access cyclin D1′s role in gene regulation.
They applied an analysis known as ChIP sequencing to study the protein’s interactions with genes that comprise the entire mouse genome, and found it occupied the regulatory region of genes governing chromosomal stability with high incidence.
They went on to show cyclin D1 promoted aneuploidy and chromosomal rearrangements typically found in cancers.
Faulty chromosomes—either too many or too few, or even ones that are the wrong shape or size—have been shown to be the crux of many cancers. However, a major question of cancer genetics is the mechanisms of CIN. What causes the breakdown in chromosomal stability?
As cyclin D1 expression is increased in the early phases of tumorigenesis, cyclin D1 may be an important inducer of CIN in tumors.
To analyze the association between CIN and cyclin D1 expression in the context of breast cancer, the team aligned an expression of a 70-gene set with the highest CIN score against over 2,000 breast cancer samples. They stratified the samples based on previously described subtypes and aligned them with cyclin D1 expression profiled across the dataset.
A significant correlation among CIN, cyclin D1 and the luminal B subtype was identified, and it was apparent that the relationship between these levels was subtype specific.
“Interestingly, previous studies have presented contradictory results,” Dr. Pestell says. “Many studies have suggested a positive correlation between cyclin D1 expression and outcomes, while others have shown reduced survival. Here, we’ve dug deep, using a genome-wide analysis, and found that overexpression of the protein appears to be directly associated with the genes involved in CIN and this correlates with the luminal B subtype.”
Drugs targeting chromosomal instability for cancer therapy have been explored, but a sub-stratification rationale for the luminal B subtype has not been established. The research presented in this study suggests such a target is worthy of further investigation.
“There is a big drive towards using targeting therapies for stratified breast cancers,” says Dr. Casimiro. “What we are thinking is that there are a growing number of drugs that target aneuploidy, like AICAR and 17-AAG, that may be used as an adjuvant therapy in patients with luminal B breast cancer.”
Richard Pestell, M.D., Ph.D., FACP, Director of the Kimmel Cancer Center at Jefferson (KCC), has been named a 2011 Fellow of the American Association for the Advancement of Science (AAAS).
As part of the Section on Medical Sciences, Dr. Pestell was elected as an AAAS Fellow for his distinguished contributions to cancer care as director of two National Cancer Institute cancer centers, including the KCC and Lombardi Cancer Center at the Georgetown University Medical Center, and research identifying new molecular targets (cyclins, acetylation) and light activated gene therapy.
Dr. Pestell is an internationally renowned expert in oncology and endocrinology, who also currently serves as Chairman of the Department of Cancer Biology, Associate Dean of Cancer Programs at Jefferson Medical College (JMC), and Vice President of Oncology Services at Thomas Jefferson University Hospital.
Election as a AAAS Fellow is an honor bestowed upon AAAS members by their peers.
Dr. Pestell, who was named Director of the KCC in November 2005, is a highly respected researcher and clinician whose current work is focused on developing new cancer therapies that specifically target tumors, and reduce the side effects that are associated with commonly used cancer treatments such as chemotherapy and radiation.
He has made significant contributions to our understanding of cell cycle regulation and the disturbances that can lead to the malignant transformation of cells. Dr. Pestell has particular expertise in hormonally-responsive tumors, such as those of the breast and prostate, and his work is directed toward the eventual discovery of novel therapies for these cancers.
This year 539 members have been awarded this honor by AAAS because of their scientifically or socially distinguished efforts to advance science or its applications. New Fellows will be presented with an official certificate and a gold and blue (representing science and engineering, respectively) rosette pin on Saturday, February 18 at the AAAS Fellows Forum during the 2012 AAAS Annual Meeting in Vancouver, B.C., Canada.
This year’s AAAS Fellows will be formally announced in the AAAS News & Notes section of the journal Science on Dec. 23.
Also, as part of the Section on Medical Sciences, Hideko Kaji, Ph.D., of the Department of Biochemistry and Molecular Biology of Thomas Jefferson University, was named a AAAS fellow for her distinguished contributions to biology by discovering specific tRNA binding to mRNA-ribosome complexes, N-terminal protein modification by arginine, and ribosome recycling, the last step of protein synthesis.
Fellows elected in previous years include Eric Wickstrom, Ph.D., a Professor of Biochemistry and Molecular Biology at JMC and member of the KCC, and Charlene J. Williams, Ph.D., of the Department of Medicine at JMC.
Researchers at the Thomas Jefferson University Hospital and Kimmel Cancer Center at Jefferson have shown that loss of the retinoblastoma tumor suppressor gene (RB) in triple negative breast cancer patients is associated with better clinical outcomes. This is a new marker to identify the subset of these patients who may respond positively to chemotherapy.
Today, no such marker is applied in care of triple negative breast cancer, and as a result, patients are all treated the same.
Agnieszka Witkiewicz, M.D., Associate Professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University, and Erik Knudsen, Ph.D., Professor of Cancer Biology and Deputy Director of Basic Science at Jefferson’s Kimmel Cancer Center, presented the findings at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium during a poster discussion on Dec. 9.
“This is a step in trying to better direct treatment for patients with triple negative breast cancer,” Dr. Knudsen said.
In general for cancer, loss of tumor suppressor genes is associated with poor clinical outcome. However, loss of RB in triple negative breast cancer patients appears to be a predictor of favorable clinical outcomes. This is because it changes the way tumor cells respond to therapy such that they end up becoming more sensitive to chemotherapy.
The researchers retrospectively evaluated the RB status and clinical outcome of a cohort of 220 patients diagnosed and treated at Thomas Jefferson University Hospital with chemotherapy. RB loss, they found, was associated with a longer overall survival. In contrast, patients with RB had worse survival.
“Triple negative breast cancer is the most deadly of breast cancers, with fast-growing tumors, that affects younger women,” said Dr. Witkiewicz. “This work allowed us to identify a marker that could lead to better treatment for patients. It’s about female personalized medicine.”
Edith Mitchell, M.D., Professor of Medical Oncology at Jefferson, and Adam Ertel, Ph.D., a research instructor in the Department of Cancer Biology, were also involved in the study.
The next step for the researchers is a clinical trial at Jefferson to confirm their findings. Tumors of newly-diagnosed patients with triple negative breast cancer will be tested for the RB gene before they receive chemotherapy. After treatment, the data will be evaluated to determine the efficacy of directing future patient care.
This study represents one important example of personalized medicine being performed at the Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University and the Kimmel Cancer Center to improve patient care.
Researchers at the Kimmel Cancer Center at Jefferson have identified cancer cell mitochondria as the unsuspecting powerhouse and “Achilles’ heel” of tumor growth, opening up the door for new therapeutic targets in breast cancer and other tumor types.
Reporting in the online Dec.1 issue of Cell Cycle, Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology & Regenerative Medicine at Thomas Jefferson University, and colleagues provide the first in vivo evidence that breast cancer cells perform enhanced mitochondrial oxidative phosphorylation (OXPHOS) to produce high amounts of energy.
“We and others have now shown that cancer is a ‘parasitic disease’ that steals energy from the host—your body,” Dr. Lisanti said, “but this is the first time we’ve shown in human breast tissue that cancer cell mitochondria are calling the shots and could ultimately be manipulated in our favor.”
Mitochondria are the energy-producing power-plants in normal cells. However, cancer cells have amplified this energy-producing mechanism, with at least five times as much energy-producing capacity, compared with normal cells. Simply put, mitochondria are the powerhouse of cancer cells and they fuel tumor growth and metastasis.
The research presented in the study further supports the idea that blocking this activity with a mitochondrial inhibitor—for instance, an off-patent generic drug used to treat diabetes known as Metformin—can reverse tumor growth and chemotherapy resistance. This new concept could radically change how we treat cancer patients, and stimulate new metabolic strategies for cancer prevention and therapy.
Investigating the Powerhouse
Whether cancer cells have functional mitochondria has been a hotly debated topic for the past 85 years. It was argued that cancer cells don’t use mitochondria, but instead use glycolysis exclusively; this is known as the Warburg Effect. But researchers at the Jefferson’s KCC have shown that this inefficient method of producing energy actually takes place in the surrounding host stromal cells, rather then in epithelial cancer cells. This process then provides abundant mitochondrial fuel for cancer cells. They’ve coined this the “Reverse Warburg Effect,” the opposite or reverse of the existing paradigm.
To study mitochondria’s role directly, the researchers, including co-author and collaborator Federica Sotgia, Assistant Professor in the Department of Cancer Biology, looked at mitochondrial function using COX activity staining in human breast cancer samples. Previously, this simple stain was only applied to muscle tissue, a mitochondrial-rich tissue.
Researchers found that human breast cancer epithelial cells showed amplified levels of mitochondrial activity. In contrast, adjacent stromal tissues showed little or no mitochondrial oxidative capacity, consistent with the new paradigm. These findings were further validated using a computer-based informatics approach with gene profiles from over 2,000 human breast cancer samples.
It is now clear that cancer cell mitochondria play a key role in “parasitic” energy transfer between normal fibroblasts and cancer cells, fueling tumor growth and metastasis.
“We have presented new evidence that cancer cell mitochondria are at the heart of tumor cell growth and metastasis,” Dr. Lisanti said. “Metabolically, the drug Metformin prevents cancer cells from using their mitochondria, induces glycolysis and lactate production, and shifts cancer cells toward the conventional ‘Warburg Effect’. This effectively starves the cancer cells to death”.
Although COX mitochondrial activity staining had never been applied to cancer tissues, it could now be used routinely to distinguish cancer cells from normal cells, and to establish negative margins during cancer surgery. And this is a very cost-effective test, since it has been used routinely for muscle-tissue for over 50 years, but not for cancer diagnosis.
What’s more, it appears that upregulation of mitochondrial activity is a common feature of human breast cancer cells, and is associated with both estrogen receptor positive (ER+) and negative (ER-) disease. Outcome analysis indicated that this mitochondrial gene signature is also associated with an increased risk of tumor cell metastasis, particularly in ER-negative (ER-) patients.
“Mitochondria are the ‘Achilles’ heel’ of tumor cells,” Dr. Lisanti said. “And we believe that targeting mitochondrial metabolism has broad implications for both cancer diagnostics and therapeutics, and could be exploited in the pursuit of personalized cancer medicine.”
A recent Science Signaling article (Science Signaling) (Pubmed Abstract), co-Senior Authored by Dr. Renato Iozzo, entitled “Signaling by the Matrix Proteoglycan Decorin Controls Inflammation and Cancer Through PDCD4 and MicroRNA-21″, was selected in the November 21st issue of Science Magazine as the Editor’s Choice (more info) in the Cell Signalling Category. Dr. Renato Iozzo is a Professor of Pathology & Cell Biology and is a member of the Kimmel Cancer Center’s Cancer Cell Biology and Signaling Research Program.
New cancer research suggests that we have misunderstood the feeding habits of cancer for decades, wrongly believing that cancer cells produce the bulk of their energy by breaking down glucose in the absence of oxygen, known as the Warburg effect.
Dr. Michael Lisanti of the Kimmel Cancer Center at Jefferson proposes that when a cell turns cancerous it begins to release hydrogen peroxide. The resulting free radicals cause oxidative damage that prompt support cells in the surrounding connective tissues, known as fibroblasts, to digest themselves.
In a New Scientist article, Dr. Lisanti explains, “It’s the Warburg effect, but in the wrong place. Cancer cells can feed off normal cells as a parasite.”
Dr. Lisanti and his team found that treating cancer cells with catalase, an enzyme that destroys hydrogen peroxide, triggered a five-fold increase in cancer cell death. The article also goes on to say that Dr. Lisanti is now gathering evidence to find out whether his ideas can be applied to many cancers or just a few.
Pancreatic cancer researchers at Thomas Jefferson University have shown, for the first time, that blocking a receptor of a key hormone in the renin-angiotensin system (RAS) reduces cancer cell growth by activating the enzyme AMPK to inhibit fatty acid synthase, the ingredients to support cell division.
With that, a new chemopreventive agent that inhibits the angiotensin II type 2 receptor—never before thought to play a role in tumor growth—could be developed to help treat one of the fastest-moving cancers that has a 5-year survival rate of only 5 percent.
Hwyda Arafat, M.D., Ph.D., associate professor of Surgery at Jefferson Medical College of Thomas Jefferson University and the co-director of the Jefferson Pancreatic, Biliary and Related Cancers Center, and her fellow researchers, including the chair of the Department of Surgery at Jefferson, Charles J. Yeo, M.D., FACS, present their findings in the August issue of Surgery.
Angiotensin II (AngII) is the principal hormone in the RAS that regulates our blood pressure and water balance; it has two receptors: type 1 and type 2. AngII is also generated actively in the pancreas and has been shown to be involved in tumor angiogenesis.
Previous studies have pointed to the hormone’s type 1 receptor as the culprit in cancer cell proliferation and tumor inflammation; however, the idea that type 2 had any effect was never entertained.
By looking at pancreatic ductal adenocarcinoma (PDA) cells in vitro, Jefferson researchers discovered that the type 2 receptor, not just type 1, mediates the production of fatty acid synthase (FAS), which has been shown to supply the cell wall ingredients necessary for cancer cells to multiply.
FAS was previously identified as a possible oncogene in the 1980s. It is up-regulated in breast cancers and is indicator of poor prognosis, and thus believed to be a worthwhile chemopreventive target.
“AngII is not just involved in cell inflammation and angiogenesis; it’s involved in tumor metabolism as well,” said Dr. Arafat, a member of the Kimmel Cancer Center at Jefferson. “It promotes FAS with both receptors, which makes the tumor grow.”
“Blocking the type 2 receptor reduces PDA cell growth with the activation of AMPK, revealing a new mechanism by which chemoprevention can exploit,” she added. “In fact, maybe combined blocking of the two receptors would be more efficient than just blocking one receptor.”
AMPK, or adenosine monophosphate-activated protein kinase, is the focus of several agents today, including ones for diabetes and related metabolic diseases. It is a master metabolic regulator for cells that is activated in times of reduced energy availability, like starvation. Activation of AMPK has been shown to improve energy homeostasis, lipid profile and blood pressure. The enzyme also activates a well-known tumor suppressor, p53.
“The main thing is activation of AMPK in tumor cells,” said Dr. Arafat. “AMPK is the perfect candidate as it regulates multiple targets that both halt tumor cell division and activate programmed cell death. Although it is yet to be determined how the type 2 receptor imposes deregulation of AMPK activity, identification of the type 2 receptor as a novel target for therapy is very exciting”
Next, Dr. Arafat and fellow researchers are proposing to take this research into animal studies. They hope to target the receptors early on in the disease to better understand its prevention capabilities and also study its treatment potential. Considering pancreatic cancer is typically detected in later stages, finding better ways to treat cases that have progressed further along would be of great benefit to patients.
Researchers at the Kimmel Cancer Center at Jefferson have shed new light on the longstanding conundrum about what makes a tumor grow—and how to make it stop. Interestingly, cancer cells accelerate the aging of nearby connective tissue cells to cause inflammation, which ultimately provides “fuel” for the tumor to grow and even metastasize.
This revealing symbiotic process, which is similar to how muscle and brain cells communicate with the body, could prove useful for developing new drugs to prevent and treat cancers. In this simple model, our bodies provide nourishment for the cancer cells, via chronic inflammation.
“People think that inflammation drives cancer, but they never understood the mechanism,” said Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology & Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the Kimmel Cancer Center. “What we found is that cancer cells are accelerating aging and inflammation, which is making high-energy nutrients to feed cancer cells.”
In normal aging, DNA is damaged and the body begins to deteriorate because of oxidative stress. “We are all slowly rusting, like the Tin-man in the Wizard of Oz,” Dr. Lisanti said. “And there is a very similar process going on in the tumor’s local environment.” Interestingly, cancer cells induce “oxidative stress,” the rusting process, in normal connective tissue, in order to extract vital nutrients.
Dr. Lisanti and his team previously discovered that cancer cells induce this type of stress response (autophagy) in nearby cells, to feed themselves and grow. However, the mechanism by which the cancer cells induce this stress and, more importantly, the relationship between the connective tissue and how this “energy” is transferred was unclear.
“Nobody fully understands the link between aging and cancer,” said Dr. Lisanti, who used pre-clinical models, as well as tumors from breast cancer patients, to study these mechanisms. “What we see now is that as you age, your whole body becomes more sensitive to this parasitic cancer mechanism, and the cancer cells selectively accelerate the aging process via inflammation in the connective tissue.”
This helps explain why cancers exist in people of all ages, but susceptibility increases as you age. If aggressive enough, cancer cells can induce accelerated aging in the tumor, regardless of age, to speed up the process.
The researchers’ findings were published in the June 1 issue of Cell Cycle in three separate papers.
One paper analyzes the gene profiles of the laser-captured connective tissue, associated with lethal tumors, in human breast cancer patients. In this paper, lethal cancers show the same gene expression pattern associated with normal aging, as well as Alzheimer’s disease. In fact, these aging and Alzheimer’s disease signatures can identify which breast cancer patients will undergo metastasis. The researchers find that oxidative stress is a common “driver” for both dementia and cancer cell spreading.
In another study, the researchers explain that cancer cells initiate a “lactate shuttle” to move lactate—the “food”—from the connective tissue to the cancer cells. There’s a transporter that is “spilling” lactate from the connective tissue and a transporter that then “gobbles” it up in the cancer cells.”
The implication is that the fibroblasts in the connective tissue are feeding cancer cells directly via pumps, called MCT1 and MCT4, or mono-carboxylate transporters. The researchers see that lactate is like “candy” for cancer cells. And cancer cells are addicted to this supply of “candy.”
“We’ve essentially shown for the first time that there is lactate shuttle in human tumors,” said Dr. Lisanti. “It was first discovered nearly 100 years ago in muscles, 15 years ago in the brain, and now we’ve shown this shuttle also exists in human tumors.”
It’s all the same mechanism, where one cell type literally “feeds” the other. The cancer cells are the “Queen Bees,” and the connective tissue cells are the “Worker Bees.” In this analogy, the “Queen Bees” use aging and inflammation as the signal to tell the “Worker Bees” to make more food.
Researchers also identified MCT4 as a biomarker for oxidative stress in cancer-associated fibroblasts, and inhibiting it could be a powerful new anti-cancer therapy.
“If lethal cancer is a disease of “accelerated aging” in the tumor’s connective tissue, then cancer patients may benefit from therapy with strong antioxidants and anti-inflammatory drugs,” said Dr. Lisanti. “Antioxidant therapy will “cut off the fuel supply” for cancer cells.” Antioxidants also have a natural anti-inflammatory action.
Identifying gene mutations in cancer patients to predict clinical outcome has been the cornerstone of cancer research for nearly three decades, but now researchers at the Kimmel Cancer Center at Jefferson have invented a new approach that instead links cancer cell metabolism with poor clinical outcome. This approach can now be applied to virtually any type of human cancer cell.
The researchers demonstrate that recurrence, metastasis, and poor clinical outcome in breast cancer patients can be identified by simply gene profiling cancer cells that are using ketones and lactate as a food supply.
These findings are reported in the April 15th online issue of Cell Cycle. The investigators are calling this new approach to personalized cancer medicine “Metabolo-Genomics.”
High-energy metabolites have long been suspected to “fuel” aggressive tumor cell behavior. The researchers used this premise to generate a gene expression signature from genetically identical cancer cells, but one cell group was fed a diet of high-energy metabolites. These lactate- and ketone-induced “gene signatures” then predicted recurrence, metastasis, and poor survival.
So, it appears that what cancer cells are eating determines clinical outcome, not necessarily new gene mutations.
Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology & Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the Kimmel Cancer Center at Jefferson, together with other researchers, found that treatment of human breast cancer cells with high-energy metabolites increases the expression of genes associated with normal stem cells, including genes upregulated in embryonic and neural stem cells.
What’s more, lactate and ketones were found to promote the growth of normal stem cells, which has critical applications for stem cell transplantation and for a host of different human diseases. It appears that these metabolites increase “stemness” in cancer cells, which drives poorer outcomes.
“Tumors that are using the body’s own nutrients (lactate and ketones) as “fuel” have a poorer outcome for patient survival, a behavior that now can be used to predict if a patient is at a high-risk for recurrence or metastasis,” Dr. Lisanti said. “This is getting to the heart of personalized cancer medicine. Now, we have identified a panel of biomarkers that directly links cancer metabolism with targeted cancer therapy.”
These findings suggest, according to the authors, that high-risk cancer patients (those whose cancer cells use high-energy metabolites) can be treated with new therapeutics that target oxidative mitochondrial metabolism, such as the antioxidant metformin, a drug that is also used to treat diabetes.
“Knowing the gene signatures of patients whose cancer cells are “eating” these metabolites for fuel is a pivotal piece of new information that we can use to diagnose and treat cancer patients,” said Martinez-Outschoorn, M.D., of the department of Medical Oncology at Thomas Jefferson University, and the lead author of the paper. “It’s not just that we know those patients will have poor survival; we know that those patients are using mitochondrial metabolism, which is the type of energy metabolism that we should be targeting with new anti-cancer drugs.”
The researchers propose that this new approach to diagnosis and subsequent treatment be called “Metabolo-Genomics” since it incorporates both cell metabolism and gene transcriptional profiling. This strategy could now be used to direct which patients receive a particular “tailored” anti-metabolic therapy.
Genetic markers, like expression of the mutationally activated HER2 gene, provide biomarkers that can be used to identify breast cancer patients at high-risk for recurrence or metastasis, and to modify their subsequent treatment with targeted therapies (i.e., herceptin, a drug used in aggressive breast cancers). But with “Metabolo-Genomics,” it is now about using “global” cancer cell metabolism for these predictions.
“Just by feeding cancer cells a particular energy-rich diet, it changes their character, without introducing mutations or altering their genetic profile,” Dr. Lisanti said. “We’ve only fed them high energy nutrients that help them to use their mitochondria, and this changes their transcriptional profile. It’s a new biomarker for “lethal” cancers that we can now treat with the right drugs, such as the antioxidant metformin.
Dr. Lisanti and his colleagues believe that tumor metabolism is the new big picture for understanding how cancers undergo recurrence and metastasis.
Researchers from the Kimmel Cancer Center at Jefferson and two other institutions have discovered new evidence that suggests the “longevity” protein SIRT1, known for its life-spanning effects in different species, can inhibit the development of a known precursor to prostate cancer, prostatic intraepithelial neoplasia (PIN).
“Prostate cancer is one of the malignancies that has a very direct relationship to aging,” says Richard G. Pestell, M.D., Ph.D., Director, Kimmel Cancer Center and Chairman of Cancer Biology at Thomas Jefferson University. “And these results provide a direct link for the first time between the onset of prostate cancer and the Sirt1 gene that regulate aging.”
Researchers from Jefferson’s Kimmel Cancer Center have genetic evidence suggesting the antioxidant drugs currently used to treat lung disease, malaria and even the common cold can also help prevent and treat cancers because they fight against mitochondrial oxidative stress—a culprit in driving tumor growth.
For the first time, the researchers show that loss of the tumor suppressor protein Caveolin-1 (Cav-1) induces mitochondrial oxidative stress in the stromal micro-environment, a process that fuels cancer cells in most common types of breast cancer.
“Now we have genetic proof that mitochondrial oxidative stress is important for driving tumor growth,” said lead researcher Michael P. Lisanti, M.D., Ph.D., professor of cancer biology at Jefferson Medical College of Thomas Jefferson University and member of the Kimmel Cancer Center at Jefferson. “This means we need to make anti-cancer drugs that specially target this type of oxidative stress. And there are already antioxidant drugs out there on the market as dietary supplements, like N-acetyl cysteine.”
These findings were published in the online February 15 issue of Cancer Biology & Therapy.
Lisanti’s lab previously discovered Cav-1 as a biomarker that functions as a tumor suppressor and is the single strongest predictor of breast cancer patient outcome. For example, if a woman has triple negative breast cancer and is Cav-1 positive in the stroma,
her survival is greater than 75 percent at 12 years, versus less than 10 percent at 5 years if she doesn’t have the Cav-1 protein, according to Dr. Lisanti.
The researchers also established Cav-1’s role in oxidative stress and tumor growth; however, where that stress originates and its mechanism(s) were unclear.
To determine this, Jefferson researchers applied a genetically tractable model for human cancer associated fibroblasts in this study using a targeted sh-RNA knock-down approach. Without the Cav-1 protein, researchers found that oxidative stress in cancer associated fibroblasts leads to mitochondrial dysfunction in stromal fibroblasts. In this context, oxidative stress and the resulting autophagy (producton of recycled nutrients) in the tumor-microenvironment function as metabolic energy or “food” to “fuel” tumor growth.
The researchers report that the loss of Cav-1 increases mitochondrial oxidative stress in the tumor stroma, increasing both tumor mass and tumor volume by four-fold, without any increase in tumor angiogenesis.
“Antioxidants have been associated with cancer reducing effects—beta carotene, for example—but the mechanisms, the genetic evidence, has been lacking,” Dr. Lisanti said. “This study provides the necessary genetic evidence that reducing oxidative stress in the body will decrease tumor growth.”
Currently, anti-cancer drugs targeting oxidative stress are not used because is it commonly thought they will reduce the effectiveness of certain chemotherapies, which increase oxidative stress.
“We are not taking advantage of the available drugs that reduce oxidative stress and autophagy, including metformin, chloroquine and N-acetyl cysteine,” Dr. Lisanti said. “Now that we have genetic proof that oxidative stress and resulting autophagy are important for driving tumor growth, we should re-consider using antioxidants and autophagy inhibitors as anti-cancer agents.”
The diabetic drug metformin and chloroquine, which is used for the prevention and treatment of malaria, prevent a loss of Cav-1 in cancer associated fibroblasts (which is due to oxidative stress), functionally cutting off the fuel supply to cancer cells.
This research also has important implications for understanding the pathogenesis of triple negative and tamoxifen-resistance in ER-positive breast caner patients, as well as other epithelial cancers, such as prostate cancers.
“Undoubtedly, this new genetically tractable system for cancer associated fibroblasts will help identify other key genetic ‘factors’ that can block tumor growth,” Dr. Lisanti said.
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