Prevent Cancer Recurrence Research Articles

Inhibition of Wnt1 expression reduces the enrichment of cancer stem cells in a mouse model of breast cancer

Breast cancer is the leading cause of deaths from cancer in women. Cancer recurrence is the most common cause of mortality in breast cancer patients. The cancer stem cell (CSC) hypothesis proposes that CSCs are the center of cancer development and recurrence. Targeting CSCs, in combination with standard chemotherapy, may prevent cancer recurrence and improve long-term survival. Stem cells can be enriched in non-adherent sphere cultures. To identify molecular targets in breast CSCs, we evaluated the transcription levels of stem cell-related genes in 4T1 mouse mammary cancer cells grown as spheres or in a monolayer culture. The most differentially expressed gene was found to be wingless-type MMTV integration site family member 1 (Wnt1) in the 4T1 sphere culture. Functionally, knockdown of Wnt1 in breast cancer cell lines suppressed the in vitro properties of the stem-like cells, including their sphere-forming ability and ALDH activity, whereas the addition of recombinant Wnt1 to breast cancer cell lines enhanced the in vitro properties of these stem-like cells. In addition, knockdown of Wnt1 in 4T1 cells affected the properties of the stem-like cells in vivo, including their tumorigenic potential and tumor initiation ability. Collectively, these results suggest that Wnt1 expression may give rise to the properties of CSCs in breast tumors. Therefore, targeting Wnt1-associated signaling proteins may provide an effective therapeutic approach for the treatment of advanced breast cancer.

Cancer stem cells and the impact of Chinese herbs, isolates and other complementary medical botanicals: a review

To elucidate the connection between the origin of certain cancers and stem cells, cancer stem cells, the stem cell niche and the tumor microenvironment, and to examine the ability of traditional Chinese herbal medicines and isolates in treating these types of cancers, the existing literature was examined and eight studies regarding Chinese herbal medicines and the prevention of cancer recurrence were critically analyzed and evaluated. Tumor stem cells may be the final target of traditional Chinese medicine. Soy flavones, ginsenoside Rg3, parthenolide, berbamine and curcumin are several examples of Chinese herbal medicines, which have been shown to be effective in the treatment of cancer, and seem to act by targeting cancer stem cells and associated pathways resulting in tumorigenesis. The treatment approaches combined with an overall treatment protocol for the tumor microenvironment and chronic systemic inflammation are likely to provide a more successful outcome than a single tactical approach. As shown in numerous studies in the literature, using complementary disciplines with orthodox treatments may enhance treatment outcomes.

Protective antitumor immunity induced by tumor cell lysates conjugated with diphtheria toxin and adjuvant epitope in mouse breast tumor models

Cancer cell vaccine-based immunotherapy has received increasing interest in many clinical trials involving patients with breast cancer. Combining with appropriate adjuvants can enhance the weak immunogenic properties of tumor cell lysates (TCL). In this study, diphtheria toxin (DT) and two tandem repeats of mycobacterial heat shock protein 70 (mHSP70) fragment 407-426 (M2) were conjugated to TCL with glutaraldehyde, and the constructed cancer cell vaccine was named DT-TCL-M2. Subcutaneous injection of DT-TCL-M2 in mice effectively elicited tumor-specific polyclonal immune responses, including humoral and cellular immune responses. High levels of antibodies against TCL were detected in the serum of immunized mice with ELISA and verified with Western blot analyses. The splenocytes from immunized mice showed potent cytotoxicity on Ehrlich ascites carcinoma cells. Moreover, the protective antitumor immunity induced by DT-TCL-M2 inhibited tumor growth in a mouse breast tumor model. DT-TCL-M2 also attenuated tumor-induced angiogenesis and slowed tumor growth in a mouse intradermal tumor model. These findings demonstrate that TCL conjugated with appropriate adjuvants induced effective antitumor immunity in vivo. Improvements in potency could further make cancer cell vaccines a useful and safe method for preventing cancer recurrence after resection.

Prevention of post-transplantation recurrence of hepatocellular carcinoma in rats with donor spleen lymphocytes infusion

Objective To explore the feasibility of using activated donor spleen lymphocytes to prevent liver cancer recurrence after liver transplantation.Methods The precursors of dendritic cells (DCs) were isolated from bone marrow of Wistar rats,and were then cultured and pulsed with CBRH7919 tumor cell antigens prepared with freeze-thawed tumor cell lysates. Spleen cells from donor (SD)/recipient (Wistar) rats were cocultured with these DCs respectively to induce CTL and to serve as the two experimental groups,C and D.Unactivited blank donor/recipient spleen cells were maintained to survive using low dose of rrIL-2.These served as the two control groups,A and B.Supernatant IFN-γ release were determined by ELISA,and the cytotoxicity of CTL was assayed by LDH release test.A post-transplantation HCC recurrence rat model was randomly assigned into five groups,6 rats each.Four groups were treated with adoptive lymphocyte infusion which came from the corresponding groups in vitro,and another group E was a saline infusion group to serve as a blank control.Tumorgenecity,tumor infiltrating-lymphocyte,and liver graft rejection were compared between the individual groups.Results The supernatant IFN-γ release level during DCs activation in group C and D were much higher than group A and B.Spleen cells in group C and D manifested much higher cytotoxicity to tumor cells than group A and B.The cytotoxicity of group D was significantly higher than group C.Aggregation of lymphocytes was detected within and near the tumor tissue with necrosis of tumor cells,and a decrease in tumorgenecity was observed in group D but without any evidence of liver graft rejection.Conclusion Activated donor spleen cells were more effective in preventing liver cancer recurrence after liver transplantation when compared with recipient spleen cells,and there was no impairment to the liver graft. Key words: Hepatocellular carcinoma; Liver transplantation; Recurrence; Dendritic cells; Immunotherapy

Are Cancer Stem Cells Responsible for Cancer Recurrence?

Are Cancer Stem Cells Responsible for Cancer Recurrence? Local recurrence or distant organ metastasis are the major causes of cancer mortality. Conventional treatments, including surgery, chemotherapy, and irradiation, do not consistently prevent cancer recurrence. Thus, an alternative therapeutic approach is needed. Recent evidence indicates a specific cell population of cancer stem cells or tumor initiating cells (jointly CSC) exists in various cancers that may be identified by cell surface markers, such as CD133, CD44, aldehyde dehydrogenase 1 (ALDH1) enzyme expression, or side population.

Proteomic Footprinting of Drug-Treated Cancer Cells as a Measure of Cellular Vaccine Efficacy for the Prevention of Cancer Recurrence

The comparative proteomic study of cell surfaces of native and drug-treated cancer cells was performed. To this end, cell proteomic footprinting, which reflects the mass spectrometry profiling of cell surface proteins, was applied to breast adenocarcinoma cells (MCF-7), which were untreated or treated with doxorubicin, tamoxifen, or etoposide. The footprints of drug-treated cells were compared with the footprints of untreated cells and the footprint of a randomly selected control cancer cell culture. It was found that drug-treated cells have reproducible, pronounced, and drug-specific changes in cell surface protein expression. Cytotoxicity assays, which are an in vitro model of human antitumor vaccination, revealed that the degree of these changes correlates directly with the ability of the cancer cells to escape cell death induced by a cytotoxic T-cell-mediated immune response. Moreover, cancer cells escape from the immune response was linearly approximated (R2 equal to 0.99) with the degree by which their proteomic footprints diverged from the footprint of the targeted (native) cancer cells. From these findings, it was concluded that the design of anticancer vaccines intended to prevent cancer recurrence after primary treatment should consider the drug-specific changes in cancer cell-surface antigens. Such changes can be easily identified by cell proteomic footprinting, renewing hopes for development of efficient cellular cancer vaccines.

Enhanced recovery programmes; coming to a hospital near you!

Enhanced recovery programmes; coming to a hospital near you!

Equivalence Is Victory

Equivalence Is Victory

Vitamin K2 does not prevent cancer recurrence

Vitamin K2 does not prevent cancer recurrence

Abstract 5020: Potential lifestyle intervention in inner city women with endometrial cancer: A pilot study

Abstract Hypothesis: Evidence suggests that modification of diet and exercise practices may prevent cancer recurrence. It may also decrease the risk factors for the leading causes of death in women including heart disease and stroke. Methods: 100 patients with previously diagnosed endometrial cancer were enrolled in a pilot study to collect data regarding current lifestyle, willingness to change and preferred programs of nutrition and exercise. All enrolled subjects were verbally asked to respond to a questionnaire that included validated and novel instruments. Results: Mean age was 64 (39-86 years) and mean body mass index was 34 kg/m2 (17-55). 38% of the responders were Black/African American, 33% were Caucasian, and 21% were Hispanic. Of these, 69% were born in the United States of America. 75% described themselves as “overweight”. The most common mode of current exercise was walking (54%). 89% of the patients responded that they would be interested in participating in a diet or exercise program. The most common reason that women stated they would want to participate was to improve overall health (48%). Only 4% stated that they thought it would prevent recurrence of their cancers. Diabetes mellitus was previously diagnosed in 30% of participants. Eighty three percent of diabetic patients had body mass index over 30 kg/m2 and 30% had body mass index over 40 kg/m2. Eleven patients currently on therapy for diabetes had hemoglobin A1C values greater then 6.5 and are at risk for microvessel damage and end-organ dysfunction including kidney failure and impaired vision Discussion: These data present the opinions of a racially heterogeneous group of women at risk for cancer recurrence, as well as the morbidity and mortality related to obesity and diabetes. These data suggest that women at our center should participate in a dietary and exercise intervention program and our patients would benefit from the additional health education. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5020. doi:10.1158/1538-7445.AM2011-5020

Abstract 4464: Ciclopirox Olamine alters PEAK-1-mediated cytoskeleton organization and invasion of metastatic cancer cells

Abstract The majority of cancer patients die from metastatic disease because there are no drugs available to prevent the spread of cancer and eradicate metastases in patients. The antimycotic drug ciclopirox olamine (CPX) is under investigation as a repositioned drug candidate which has anti-tumor and anti-angiogenesis activity in experimental models. Because CPX has been FDA tested and shows exceptionally low side effects in patients even at high doses, it has significant potential as both a therapeutic to prevent cancer recurrence after surgical resection and for the long term systemic treatment of cancer patients with overt metastatic disease. However, CPX has not yet been tested for its ability to inhibit metastatic cell function. In this study we examined the ability of CPX to inhibit metastatic cancer cell migration, invasion, and proliferation, and evaluated the signal transduction pathways that regulate these processes. Interestingly, CPX was observed to inhibit the expression of the tyrosine kinase, pseudopodium-enriched atypical kinase 1 (PEAK1), which is necessary for proper remodeling of the actin cytoskeleton and focal adhesion dynamics in metastatic cancer cells (PNAS, 107(24), 10920-5). Associated with the decrease in PEAK1 expression by CPX was decreased total cellular tyrosine phosphoprotein content, pseudopodium protrusion, cancer cell spreading, movement, and proliferation on extracellular matrix proteins. Collectively, our findings indicate that at therapeutic doses, CPX potently alters cytoskeletal signaling, cancer cell movement, and proliferation by modulating PEAK1 activity. These findings are important in light of the fact that PEAK1 amplification and cytoskeleton modulation have been linked to anchorage-independent cell growth, cell migration, and tumor progression in human gastrointestinal cancers. The exceptional safety record of CPX and our findings support the notion that CPX has significant potential as a repositioned therapeutic agent to combat cancer recurrence and spread in patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4464. doi:10.1158/1538-7445.AM2011-4464

Do antidepressants reduce the effectiveness of tamoxifen?†

Because of the relatively significant incidence of both clinical depression and debilitating hot flashes (20%–30%), clinicians caring for women with breast cancer who are taking tamoxifen for the treatment or prevention of cancer recurrence are often faced with the need to prescribe antidepressant medications concurrently with tamoxifen. Over the past 5 years, a growing number of studies have raised questions regarding the interaction of antidepressants and tamoxifen, particularly the following question: ‘Do antidepressants reduce the effectiveness of tamoxifen treatment?’ At issue is the extent of the clinical impact of cytochrome P450 2D6 (CYP2D6) inhibitors, in the form of several antidepressants (particularly several of the serotonin reuptake inhibitors, or SSRIs) on the effectiveness of tamoxifen.

The benefits of discussing adjuvant therapies one at a time instead of all at once

Breast cancer patients must often decide between multiple adjuvant therapy options to prevent cancer recurrence. Standard practice, as implemented in current decision support tools, is to present information about all options simultaneously, but psychology research suggests that sequential decision processes might improve decision making. We tested whether asking women to consider hormonal therapy and chemotherapy separately would improve women's risk knowledge and/or affect treatment intentions. We conducted an Internet-administered experimental survey of a demographically diverse sample of 1,781 women ages 40-74. Participants were randomized to experience a standard, comprehensive decision process versus sequential (one at a time) decisions regarding adjuvant therapy options for a hypothetical breast cancer patient with an estrogen receptor-positive (ER+) tumor. We assessed comprehension of key statistics, perceptions of treatment effectiveness, and perceived interest in adjuvant chemotherapy, as well as participants' numeracy levels. When participants made sequential decisions, they demonstrated greater comprehension of decision-relevant risk statistics, as compared to when they made decisions all at once (all P's < 0.001). Among higher-numeracy participants, those making sequential decisions were less interested in chemotherapy (P < 0.001). Lower-numeracy participants who considered all options simultaneously were insensitive to the degree of risk reduction, but those who made sequential decisions were sensitive (P = 0.03). In conclusion, presenting adjuvant therapy options sequentially improves women's comprehension of incremental treatment benefit and increases less numerate women's sensitivity to the magnitude of the achievable risk reduction over standard, all at once approaches. Sequential approaches to adjuvant therapy decisions may reduce use of chemotherapy among those at low risk for recurrence.

Ultra sensitive biosensor based on impedance spectroscopy at microwave frequencies for cell scale analysis

This paper presents an original approach for biological cell discrimination using impedance spectroscopy analysis at microwave frequencies. The proposed method allows label-free analysis at the cell scale using high frequency electromagnetic waves as a non-invasive probe to analyze the intracellular medium. In the present case, the biosensor design takes advantage of classical planar microwave filter topology, where coupling zones present high sensitivity to tiny dielectric perturbations. With proper design, these specific areas can be used as an electromagnetic (EM) detector. In the present work, biosensor sensitivity allows reaching selective biological sample detection and bio-impedance measurements down to single-cell analysis. As presented in this paper, this concept has been experimentally validated with characterisations conducted on biological cancerous stem cells (cells considered at a low differentiation degree) and U87 glial cells (differentiated cells); both coming from human nervous system. Stem cells are almost similar in shape and size as differentiated cells. They are therefore quite difficult to identify using a microscope, and studies focusing on their differentiation mechanisms are very challenging. Cell chemical labeling would have been suitable if we would have been sure that used label will not induce an unwanted cell differentiation. To the contrary, EM impedance measurements show a significant difference between stem and differentiated cells dielectric permittivity. Therefore, such measurements can be an efficient approach to determine cell differentiation degree in a non-invasive way. As a label-free approach, the high frequency impedance spectroscopy could be very interesting for accurate discrimination of un-differentiated cells. Indeed, stem cells are currently the subject of a large research effort in the biologist community; especially in case of cancers, where cancerous stem cells are suspected to be the origin of most of tumor recurrences. Hence, based on this identification technique, a new diagnostic analysis could be developed for early cancer recurrence prevention.

CD137 agonist antibody prevents cancer recurrence: contribution of CD137 on both hematopoietic and nonhematopoietic cells

AbstractAntigen-specific memory T cells (Tms) are essential in the immune surveillance of residual and metastatic tumors. Activation of Tms requires designing vaccines based on tumor rejection antigens, which are often not available to cancer patients. Therefore, it is desirable to have a general applicable approach to activate Tms without extensive knowledge of tumor antigens. Here, we report that activation of antigen-specific Tms could be achieved by the administration of agonistic anti-CD137 monoclonal antibody without additional tumor vaccination, leading to the prevention of recurrence and metastases after surgical resection of primary tumors in mouse models. By reconstitution with CD137-deficient Tms, we demonstrate that expression of CD137 on antigen-specific Tms is only partially required for the effect of anti-CD137 antibody. Other host cells, including those from hematopoietic and nonhematopoietic origins, are also important because ablation of CD137 from these cells partially but significantly eliminates antitumor effect of anti-CD137 antibody. Our findings implicate a potential new approach to prevent recurrence and metastases in cancer patients.

Cancer Vaccines: Emphasis on Pediatric Cancers

The success that vaccines have had in the fight with infectious diseases has not been mirrored in their use in the fight against cancer. The major differences are that cancer vaccines have been tested in the therapeutic rather than the prophylactic setting, and in older adults rather than in the pediatric population. Cancers, as well as current standard treatments, are highly immunosuppressive, which further compromises the success of therapeutic vaccines. Cancer is considered to be primarily a disease of the older age and yet many children suffer from or succumb to cancers such as leukemias, glioblastomas, neuroblastomas and sarcomas. Standard therapy, even when curative, is accompanied by serious side effects, including secondary tumors later in life. Due to the greater capacity of a young immune system to recover after cancer treatment, therapeutic vaccines are expected to have a better chance to elicit protective immunity and prevent cancer recurrence in children. In this review, we discuss the current efforts at designing and testing cancer vaccines in children with the focus on specific tumor antigens expressed by pediatric cancers.

Secondary Prevention of Colorectal Cancer: Is There an Optimal Follow-up for Patients with Colorectal Cancer?

Secondary prevention of colorectal cancer, as opposed to primary prevention, indicates that a person has already had the disease and there are steps being taken to prevent cancer recurrence, usually as metachronous tumors. This generally involves annual surveillance with colonoscopy after surgical removal of the initial cancer if some aspect of the colon remains. However, some familial cases may involve other modalities, such as cyclooxygenase inhibitors, as an adjunct after the initial operation. Genetic testing in suspected familial cases may identify candidates for secondary prevention. The timing for secondary prevention is critical to prevent recurrent advanced disease, which is detrimental to patient survival. Recommendations are often empiric, but some cases are based on the biological behavior of the tumor. Close follow-up with a competent health care provider, such as a gastroenterologist, is necessary to help prevent recurrence.

Abrogation of Local Cancer Recurrence After Radiofrequency Ablation by Dendritic Cell-based Hyperthermic Tumor Vaccine

Local recurrence is a therapeutic challenge for radiofrequency ablation (RFA) in treatment of small solid focal malignancies. Here we show that RFA induced heat shock proteins (HSPs) expression and high mobility group box-1 (HMGB1) translocation in xenografted melanoma, which might create a proinflammatory microenvironment that favors tumor antigen presentation and activation of the effector T cells. On this basis, we investigate whether a prime-boost strategy combining a prime with heat-shocked tumor cell lysate-pulsed dendritic cell (HT-DC) followed by an in situ boost with radiofrequency thermal ablation can prevent local tumor recurrence. The combination treatment with HT-DC and RFA showed potent antitumor effects, with >or=90% of tumor recurrence abrogated following RFA treatment. By contrast, prevaccination with unheated tumor lysate-pulsed DC had little effect on tumor relapse. Analysis of the underlying mechanism revealed that splenocytes from mice treated with HT-DC plus RFA contained significantly more tumor-specific, IFN-gamma-secreting T cells compared with control groups. Moreover, adoptive transfer of splenocytes from successfully treated tumor-free mice protected naive animals from tumor recurrence following RFA, and this was mediated mainly by CD8(+) T cells. Therefore, the optimal priming for the DC vaccination before RFA is important for boosting antigen-specific T cell responses and prevention of cancer recurrence.

Prevention of cancer recurrence after treatment for hepatitis C virus-related hepatocellular carcinoma by interferon therapy.

The outcome of treatment for hepatitis C virus-related hepatocellular carcinoma is still unsatisfactory because of the high rate of recurrence of cancer, including intrahepatic metastasis and multicentric carcinogenesis after treatment. The rate of recurrence, especially that of multicentric carcinogenesis, is affected by persistent active hepatitis and hepatic fibrosis caused by chronic hepatitis C. Interferon therapy improves the outcome after treatment of hepatocellular carcinoma by decreasing recurrence and preserving or improving liver function when treatment is successful. Radical treatment by anatomic resection and interferon therapy can markedly improve the outcome in patients with hepatitis C virus-related hepatocellular carcinoma.

Abstract PL04-03: What it takes to sustain consumer health informatics

Abstract PL04-03 People facing a cancer diagnosis are a very important target for consumer health informatics. Life-threatening diagnosis, painful and disruptive treatments, turmoil in personal relationships, paralyzing anxiety, and a diminished sense of self call up a host of new needs. And at least some research shows that their needs for information are less well-met than their care delivery or support needs CHESS (the Comprehensive Health Enhancement Support System) is a web-based integrated communication system providing a wide range and depth of information, ways of connecting to others in the same situation, and tools for analysis and self-management. After describing the system, this presentation on the University of Wisconsin’s CECCR will summarize research on how CHESS has been able to buffer or prevent many of the psychosocial consequences of cancer diagnosis and treatment on patients and their families. One just-completed trial with lung cancer patients also found life prolonged for several months, as compared to patients whose needs were only served by the Internet in general. Recent innovations within CHESS focus on integrating our web-based tools with existing human resources, such as human information experts, caregivers, and clinical staff. Next steps for us include achieving broad dissemination within a large HMO, replicating the life-prolonging effects and understanding how patient and caregiver behaviors created them, and using a cell-phone based system to prevent cancer recurrence through lifestyle changes and self-management. A parallel research effort at Wisconsin has explored barriers to implementing such a system within health-care organizations (see the 2007 book, Investing in e-Health, by Gustafson, Brennan, and Hawkins for more detail). A fundamental issue is that the benefits of consumer health informatics reside primarily if not exclusively within consumers (i.e., individual patients and their families), but those best able to refer consumers to high-quality health informatics are clinicians and health care organizations. Thus, the primary decision makers on disseminating consumer health informatics get no direct benefit from it, and processes for such referral risk instead being a burden on individual clinicians and the health care organization generally. Our research constructed and validated a model of how consumer health informatics such as CHESS are implemented within health care organizations, identifying seven factors (each with multiple indicators) that could contribute to or block success of an implementation over time: 1) organizational environment, 2) organizational motivation, 3) technology usefulness, 4) promotion, 5) implementation process, 6) department-technology fit, and 7) key personnel awareness and support. We then conducted six thorough case studies of organizations that had begun CHESS implementations for their patients/clients over more than a decade to try to understand the relative importance of the factors and how they interacted. It was clear that no one or two factors alone could produce success or failure, even though there are some that are clearly strong positives or negatives. Rather, a successful implementation relied on at least some strength on a clear majority of the factors, which suggests that model factors may be compensatory to each other. Thus, an institution planning to implement consumer health informatics might find success by strengthening already strong factors as well as building up weak ones. Citation Information: Cancer Prev Res 2008;1(7 Suppl):PL04-03.