Spontaneous Tumor Regression Research Articles

ATM-dependent spontaneous regression of early Eμ-myc–induced murine B-cell leukemia depends on natural killer and T cells

AbstractMechanisms of spontaneous tumor regression have been difficult to characterize in a systematic manner due to their rare occurrence and the lack of model systems. Here, we provide evidence that early-stage B cells in Eμ-myc mice are tumorigenic and sharply regress in the periphery between 41 and 65 days of age. Regression depended on CD4+, CD8+, NK1.1+ cells and the activation of the DNA damage response, which has been shown to provide an early barrier against cancer. The DNA damage response can induce ligands that enhance immune recognition. Blockade of DNAM-1, a receptor for one such ligand, impaired tumor regression. Hence, Eμ-myc mice provide a model to study spontaneous regression and possible mechanisms of immune evasion or suppression by cancer cells.

Molecular genetic, cardiac and neurodevelopmental findings in cases of prenatally diagnosed rhabdomyoma associated with tuberous sclerosis complex

Rhabdomyoma is the most common type of cardiac tumor in fetuses and is often associated with tuberous sclerosis complex (TSC) with neurologic sequelae. The purpose of this study was to investigate the cardiac and neurodevelopmental outcomes of fetal rhabdomyoma. We reviewed the clinical characteristics of 23 cases of cardiac rhabdomyoma diagnosed prenatally by fetal echocardiography at the Asan Medical Center between January 1998 and December 2009. We also reviewed postnatal results of brain magnetic resonance imaging, echocardiography, renal ultrasound examination and molecular genetic analysis to confirm the presence of cardiac rhabdomyoma with or without TSC. Among 23 cases, outcome data were available for 17 (73.9%) and six cases (26.1%) were lost to follow-up. The survival rate was 100.0% (17/17). Among the 17 cases with outcome data, spontaneous tumor regression occurred in eight (47.1%), and no change in tumor size and number was observed in the remaining nine cases (52.9%). There was no evidence of long-term cardiac dysfunction caused by persisting rhabdomyomas, regardless of tumor size. TSC was found in nine patients (52.9%), of whom five (55.6%) showed neurodevelopmental morbidity. We identified mutations in one of the TSC1 or TSC2 genes in four of nine TSC infants whose parents allowed us to perform molecular genetic analysis. Three of these (75.0%) were found to have neurologic impairment. Seven (77.8%) of nine TSC cases were non-familial. The overall outcome of isolated cardiac rhabdomyoma appears to be favorable. We suggest that systematic postnatal evaluation of TSC be performed even in cases of cardiac rhabdomyoma without a family history of TSC. Molecular characterization of TSC1 and TSC2 might be helpful in predicting short- and long-term neurodevelopmental outcomes.

Spontaneous Regression of Non-Small Cell Lung Cancer in a Patient with Idiopathic Pulmonary Fibrosis: A Case Report

Treatment of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) is difficult because the mortality rate after surgery or chemotherapy is high for these patients. Spontaneous regression of cancer is rare, especially in lung cancer. A 62-year-old man, previously diagnosed with IPF, presented with stage IIIC (T2N3M0) non-small cell lung cancer. About 4 months later, spontaneous regression of the primary tumor was observed without treatment. To the best of our knowledge, this is the first report of spontaneous regression of lung cancer in a patient with IPF.

Family Multiple Pituitary Deficiencies Associated to Pituitary Process: Which Diagnosis?

The hypopituitarism of children, partial or absolute, stems from many causes. Tumor cause, such as craniopharyngioma, is predominant and must always be sought. The presence of a pituitary lesion in a child with a GH deficiency, especially in family forms, should not overlook the possibility of a concomitant genetic disorder, in particular mutation of Prop 1. Surgical abstention in this case, with morphological and ophthalmologic monitoring are shown because the spontaneous regression of the hyperplasia pseudo tumor . We report two cases in this clinical regard. Keywords: pituitary insufficiency, GH deficiency, pituitary hyperplasia, Mutation of Prop. 1.

Gene-expression profiling to identify genes related to spontaneous tumor regression in a canine cancer model

Microarray transcriptome study in cancer has been commonly used to investigate tumorigenic mechanisms. The unique growth pattern of spontaneous regression (SR) after progressive (P) growth in canine transmissible venereal tumor (CTVT) provides a valuable cancer model to study the genome-wide differences in samples between the two stages of growth. In this study, Affymetrix analysis was performed based on the canine genome to compare the gene expression profiles of CTVT P- and SR-phase tumors. A total of 459 (278 up-regulated and 181 down-regulated) genes were identified as being differentially-expressed during the SR phase by the 2-fold method. Further analysis of these genes revealed that the expression of three genes associated with IL-6 production –TIMD-4, GPNMB and PLTP – was significantly higher in SR-phase tumors than in P-phase tumors; these results were also confirmed by real time RT-PCR in tumor tissues of beagles. In addition, we found that Th17-related genes were over-expressed in the SR phase, suggesting autoimmune responses involvement in tumor regression. Although the interaction between CTVT and host immunity were partially investigated in previous studies, our results enable us to gain new insight into the genes and possible mechanisms involved in tumor regression and reveal potentially useful targets for cancer therapy.

Characterization of three newly established rat sarcoma cell clones

Establishment of new animal models using selected cell lines with different behaviour is very important for cancer investigations. In this study, we describe three morphologically distinct rat sarcoma clones-C4, C7 and D6-isolated from the R5-28 cell line. Cells of all clones expressed vimentin, fibronectin, laminin, collagen IV and matrix metalloproteinases 2 and 9. However, desmin, cytokeratins 8 and 18, ZO-1 and desmoplakins I and II were not detected. Significant proliferative capacity was documented by proliferating cell nuclear antigen expression and BrdU positivity. Karyotype of the C4, C7 and D6 cells greatly differed from diploid chromosome number of normal rat somatic cells. High expression of three cytokines-monocyte chemoattractant protein 1, tissue inhibitor of metalloproteinases 1 and vascular endothelial growth factor-was observed in all three clones. However, they varied in concentration of chemokines associated with neutrophil migration and activation-cytokine induced neutrophil chemoattractant 2 and lipopolysaccharide induced CXC chemokine. The C4 clone showed spontaneous tumour regression in vivo that was associated with significant changes in lymphocyte subpopulations.

Case of spontaneous regression of carotid body tumor in a SDHD mutant: a discussion on potential mechanisms based on a review of the literature

BackgroundHead and neck paragangliomas are tumors associated with the parasympathetic nerve system and typically show an indolent growth pattern. Therefore a conservative management strategy is considered in selected cases.Methods and resultsWe present a case of a female patient who presented in 2003 with bilateral carotid body tumors and a tympanic tumor, associated with a mutation in the succinate dehydrogenase -sub-unit-D (SDHD). She was operated on the right carotid body tumor and the tympanic tumor. Thereafter the follow-up was performed with MR examinations at 2-year intervals. After an initial stable phase, over the last 3 years a spontaneous near-total regression of the contralateral carotid body tumor was observed, with only subtle rest-abnormalities visible in 2011.ConclusionsThe present case underlines the indolent growth pattern of head and neck paragangliomas and for the first time describes a rare manifestation of spontaneous regression of a carotid body tumor. The literature was reviewed to discuss this phenomenon.

Krüppel-like factor 4 (KLF4) suppresses neuroblastoma cell growth and determines non-tumorigenic lineage differentiation

Neuroblastoma (NB) is an embryonal tumor and possesses a unique propensity to exhibit either a spontaneous regression or an unrestrained growth. However, the underlying mechanism for this paradoxical clinical outcome remains largely unclear. Quantitative RT-PCR analysis on 102 primary NB tumors revealed that lower Krüppel-like factor 4 (KLF4) expression is frequently found in the unfavorable NB (Mann-Whitney test, P=0.027). In particular with the high-risk factors such as age of patient >1 year, MYCN amplification and low TRKA expression, the decreased expression of KLF4 was significantly associated with an unfavorable NB outcome. Despite knockdown of KLF4 alone is not sufficient to increase tumorigenicity of NB cells in vivo, stable expression of KLF4 short hairpin RNA in Be(2)-C cells significantly promoted growth of NB cells and inhibited cell differentiation toward fibromuscular lineage. In concordant with these observations, overexpression of KLF4 in SH-SY-5Y cells profoundly suppressed cell proliferation by direct upregulation of cell-cycle inhibitor protein p21(WAF1/CIP1), and knocking down p21(WAF1/CIP1) could partially rescue the suppressive effect of KLF4. Importantly, KLF4 overexpressing cells have lost their neuroblastic phenotypes, they were epithelial-like, strongly substrate-adherent, expressing smooth muscle marker and became non-tumorigenic, suggesting that KLF4 expression is crucial for lineage determination of NB cells, probably, favoring spontaneous tumor regression. Subsequent global gene expression profiling further revealed that transforming growth factor beta (TGFβ) and cell-cycle pathways are highly dysregulated upon KLF4 overexpression, and myogenic modulators, MEF2A and MYOD1 were found significantly upregulated. Taken together, we have demonstrated that KLF4 contributes to the favorable disease outcome by directly mediating the growth and lineage determination of NB cells.

Pulmonary Metastatic Giant Cell Tumors Presenting as Totally Hyalinized and Ossified Nodules

We report a case of giant cell tumor of the left distal femur with simultaneous bilateral pulmonary metastases. Pathologic examination of the left lung nodule showed a metastatic giant cell tumor with a noncontinuous ossified rim, and the right lung nodules were totally hyalinized or ossified without residual giant cell tumor components. Hyalinization was a consistent finding in both the primary bone lesion and the pulmonary metastases. Because the patient did not receive chemotherapy or radiotherapy before her surgical procedure, we believe that these changes represent spontaneous tumor regression.

Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model

The Sonic Hedgehog (Shh) pathway drives a subset of medulloblastomas, a malignant neuroectodermal brain cancer, and other cancers. Small-molecule Shh pathway inhibitors have induced tumor regression in mice and patients with medulloblastoma; however, drug resistance rapidly emerges, in some cases via de novo mutation of the drug target. Here we assess the response and resistance mechanisms to the natural product derivative saridegib in an aggressive Shh-driven mouse medulloblastoma model. In this model, saridegib treatment induced tumor reduction and significantly prolonged survival. Furthermore, the effect of saridegib on tumor-initiating capacity was demonstrated by reduced tumor incidence, slower growth, and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors. Saridegib, a known P-glycoprotein (Pgp) substrate, induced Pgp activity in treated tumors, which likely contributed to emergence of drug resistance. Unlike other Smoothened (Smo) inhibitors, the drug resistance was neither mutation-dependent nor Gli2 amplification-dependent, and saridegib was found to be active in cells with the D473H point mutation that rendered them resistant to another Smo inhibitor, GDC-0449. The fivefold increase in lifespan in mice treated with saridegib as a single agent compares favorably with both targeted and cytotoxic therapies. The absence of genetic mutations that confer resistance distinguishes saridegib from other Smo inhibitors.

Tumeurs épithéliales thymiques de régression spontanée

Spontaneous regression of an epithelial thymic tumour has been reported but seems extremely rare. Its mechanism is unknown. We report two cases of epithelial thymic tumour, either histologically proven or highly suspected on imaging, that regressed spontaneously (partially in one patient and totally in the other). Spontaneous regression of an epithelial thymic tumour is very rare but this possibility could lead to clinical and radiological monitoring rather than surgery in selected patients.

Abstract 1885: Targeting the FOXO1/KLF6 transcriptional network to modulate response to anti-EGFR based therapy

Abstract Epidermal growth factor receptor (EGFR) activation is both a key molecular driver of disease progression and the target of a broad class of molecular agents designed to treat advanced cancer. Nevertheless, resistance develops through several mechanisms including constitutive activation of AKT signaling. Additional molecular characterization of the downstream mediators of EGFR signaling may lead to the development of new classes of targeted molecular therapies to treat resistant disease. Here we identify a transcriptional network involving the KLF6 and FOXO1 tumor suppressor genes that negatively regulate activated EGFR signaling and that can be reactivated using the combination of two FDA approved agents in both cell culture and in vivo models of the disease. In both murine models and patient derived lung adenocarcinoma samples, EGFR activation is associated with FOXO1 mislocalization and decreased KLF6 expression. Furthermore, in a Kras driven mouse model, KLF6 expression is not significantly changed whereas AKT activation seen in the Pten/Mmac1+/− heterozygous mouse model results in FOXO1 mislocalization and decreased KLF6 expression. Consistent with these findings, inhibition of AKT signaling promotes increase in nuclear FOXO1 resulting in transactivation of the KLF6 tumor suppressor gene in lung adenocarcinoma cell lines. Correspondingly, the EGFRL858R mouse model demonstrates spontaneous tumor regression when treated with the anti-EGFR based therapy, erlotinib, an FDA-approved small-molecule inhibitor of EGFR signaling. We analyzed L858R mouse tumors samples treated with erlotinib and found increased KLF6 expression following EGFR inhibition. Conversely, targeted reduction of KLF6 resulted in decreased erlotinib response in both cell culture and in vivo models of disease suggesting a direct link between KLF6 upregulation and the induction of apoptosis by anti-EGFR based therapy. Therefore, we hypothesized that acquired resistance to anti-EGFR based therapies could be overcome by restoring downstream function of the FOXO1/KLF6 transcriptional network. Here we demonstrate that an FDA-approved drug, trifluoperazine hydrochloride (TFP), which has been shown to inhibit FOXO1 nuclear export, restores sensitivity to AKT-driven erlotinib-resistance through modulation of the KLF6/FOXO1 signaling cascade in both cell culture and xenograft models. Furthermore, silencing of FOXO1 blunts apoptosis mediated through combination erlotinib and TFP treatment suggesting that this transcriptional network is important for negatively regulating AKT signaling. Combined, these studies define a novel transcriptional network regulating oncogenic EGFR signaling and identify a class of FDA-approved drugs with the potential for rapid clinical translation to restore chemosensitivity to anti-EGFR-based therapy for the treatment of metastatic lung adenocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1885. doi:1538-7445.AM2012-1885

Small-cell Lung Cancer Exhibiting Spontaneous Regression

A 56-year-old woman was admitted to our hospital because a chest X-ray and thoracic computed tomography (CT) scan revealed a heterogeneous tumor in the middle mediastinum during a visit to a nearby clinic for a consultation regarding a persistent cough and body weight loss. However, the tumor spontaneously decreased on thoracic CT performed on admission. Subsequently, a biopsy of the tumor using video-assisted thoracoscopy was performed. The pathological findings disclosed the tumor to be small-cell lung cancer with infiltration of CD8-positive T-cells exhibiting spontaneous regression. Cell-mediated immunity, including CD8-positive T-cells, may have relevance to the spontaneous regression of malignant tumors.

Induction of Abscopal Anti-Tumor Immunity and Immunogenic Tumor Cell Death by Ionizing Irradiation - Implications for Cancer Therapies

Although cancer progression is primarily driven by the expansion of tumor cells, the tumor microenvironment and anti-tumor immunity also play important roles. Herein, we consider how tumors can become established by escaping immune surveillance and also how cancer cells can be rendered visible to the immune system by standard therapies such as radiotherapy or chemotherapy, either alone or in combination with additional immune stimulators. Although local radiotherapy results in DNA damage (targeted effects), it is also capable of inducing immunogenic forms of tumor cell death which are associated with a release of immune activating danger signals (non-targeted effects), such as necrosis. Necrotic tumor cells may result from continued exposure to death stimuli and/or an impaired phosphatidylserine (PS) dependent clearance of the dying tumor cells. In such circumstances, mature dendritic cells take up tumor antigen and mediate the induction of adaptive and innate anti-tumor immunity. Locally-triggered, systemic immune activation can also lead to a spontaneous regression of tumors or metastases that are outside the radiation field - an effect which is termed abscopal. Preclinical studies have demonstrated that combining radiotherapy with immune stimulation can induce anti-tumor immunity. Given that it takes time for immunity to develop following exposure to immunogenic tumor cells, we propose practical combination therapies that should be considered as a basis for future research and clinical practice. It is essential that radiation oncologists become more aware of the importance of the immune system to the success of cancer therapy.

Spontaneous regression of pancreatic cancer: Real or a misdiagnosis?

Spontaneous tumor regression has been subject of numerous studies and speculations for many years. This phenomenon is exceptional, but well reported, in some types of tumors, but not in pancreatic cancer. Pancreatic cancer has the worst five-year survival rate of any cancer. Despite numerous molecular studies and clinical approaches, using several mouse models, this cancer responds poorly to the existing chemotherapeutic agents and progress on treatment remains elusive. Although pancreatic cancer tumors seldom undergo spontaneous regression, and some authors take that with skepticism, there are some cases reported in the literature. However, the variability in the description of the reports and technical details could make this process susceptible to misdiagnosis. Distinguishing between different types of pancreatic carcinoma should be taken with caution as they have wide differences in malignant potential. Diseases such as pancreatic benign tumors, insulinomas, or autoimmune pancreatitis could be responsible for this misdiagnosis as a pancreatic cancer. Here we review different cases reported, their clinical characteristics, and possible mechanisms leading to spontaneous regression of pancreatic cancer. We also discuss the possibilities of misdiagnosis.

Malignant Ovarian Tumors with Induced Expression of Carbonyl Reductase Show Spontaneous Regression

BackgroundThe present study investigated tumor proliferation in a tumor model using murine ovarian cancer cells with increased carbonyl reductase (CR) expression.MethodsCR cDNA was transfected into murine T-Ag-MOSE ovarian cancer cells by lipofection. CR-transfected cells (CR induction group) or empty vector-treated cells (control group) were injected into the backs of 8-week-old nude mice at a concentration of 0.5 × 106 per 0.2 mL. Subsequent tumor proliferation in both groups was observed for 5 weeks.ResultsThe control group showed an increase in tumor volume during the 5 weeks of observation. However, tumor volume in the CR induction group increased up to the second week but then decreased continuously until the fifth week of observation. The tumor growth curves for the two groups showed a significant difference (Mann-Whitney U test, P < 0.001). Histological and biochemical experiments were performed using tumor tissues isolated in the third week. Necrosis and inflammatory cell infiltration were noted for tumors in the CR induction group. Also, the number of apoptotic cells was significantly increased in the CR induction group compared with the control group (P < 0.001). Milk fat globule EGF factor 8, an “eat-me” signal for phagocytes such as macrophages, was expressed extensively in the tumor cytoplasm and interstitial cells of the CR induction group, and engulfment of apoptotic cells by macrophages was observed. Vascular endothelial growth factor expression in tumors was notably decreased in the CR induction group compared with the control group.ConclusionIncreased necrosis due to engulfing of apoptotic cells by phagocytes attracted by increased milk fat globule EGF factor 8 was considered to be the mechanism of spontaneous tumor regression in the CR induction group.

Upper Gastrointestinal Bleeding as Initial Presentation of Burned-out Testicular Tumor

We report a case of 33-year-old man who initially presented with upper gastrointestinal bleeding caused by metastatic testicular can- cer. Physical examination was significant for a palpable abdominal mass. Emergency gastroduodenoscopy yielded an ulcerated in- filtrating mass in the third portion of the duodenum. Computerized tomography of the abdomen demonstrated a retroperitoneal mass. Histological examination of the retroperitoneal mass biopsy showed a nonseminamatous germ cell tumor consisting of embr- yonal cell carcinoma. Examination of the testes revealed a normal-sized firm left testis, and a normal right one. Ultrasonography of the testes showed multiple left testicular calcifications. The patient underwent left radical inguinal orchiectomy and histological exa- mination of the resected testis showed spontaneous regression of testicular germ cell tumor. We suppose that the tumor was a so- called 'burned-out' testicular tumor. He was treated with four courses of chemotherapy with cisplatin, etoposide and bleomycin. At five year follow-up, the patient was doing well, with no recurrens.

OP35.03: Fetal cardiac rhabdomyoma: short‐term and long‐term outcome

Objectives: Rhabdomyoma is the most common type of cardiac tumor in fetuses and is often associated with tuberous sclerosis complex (TSC) with neurologic sequelae. The purpose of this study is to investigate short-term and long-term outcome of fetal cardiac rhabdomyoma. Methods: We analyzed the clinical characteristics of 23 cases prenatally diagnosed with cardiac rhabomyomas on fetal echocardiography at Asan Medical Center between January 1998 and December 2009. We performed postnatal workup including brain magnetic resonance imaging (MRI), echocardiography, abdominal ultrasonography and molecular genetic analysis to confirm the presence of cardiac rhabdomyomas associated with or without TSC. Results: Among 23 cases, 17 cases (74%) had available outcome and 6 cases (26%) were lost to follow-up. 1) The survival rate was 100% (17/17). 2) Among 17 cases, while spontaneous tumor regression occurred in 11 cases (65%), no change in tumor size and number was observed in the remaining 6 cases (35%). 3) There was no evidence of long-term cardiac dysfunction due to remnant rhabdomyomas, regardless of tumor size. 4) TSC was revealed in 9 patients (53%), of whom four (44%) showed neurodevelopmental morbidities. 5) Among 4 patients with neurologic impairment, three (75%) had TSC gene (TSC1/TSC2) mutation. 6) Seven (78%) of 9 TSC cases were non-familial. Conclusions: The overall outcome of isolated cardiac rhabdomyomas was favorable. We suggest that systematic evaluation of TSC be performed even in cases of cardiac rhabdomyomas without family history of TSC. Molecular diagnosis of TSC1 and TSC 2 might be helpful in predicting short-term and long-term neurodevelopmental outcome.

Expression of anti-HVEM single-chain antibody on tumor cells induces tumor-specific immunity with long-term memory

Genetic engineering of tumor cells to express immune-stimulatory molecules, including cytokines and co-stimulatory ligands, is a promising approach to generate highly efficient cancer vaccines. The co-signaling molecule, LIGHT, is particularly well suited for use in vaccine development as it delivers a potent co-stimulatory signal through the Herpes virus entry mediator (HVEM) receptor on T cells and facilitates tumor-specific T cell immunity. However, because LIGHT binds two additional receptors, lymphotoxin β receptor and Decoy receptor 3, there are significant concerns that tumor-associated LIGHT results in both unexpected adverse events and interference with the ability of the vaccine to enhance antitumor immunity. In order to overcome these problems, we generated tumor cells expressing the single-chain variable fragment (scFv) of anti-HVEM agonistic mAb on the cell surface. Tumor cells expressing anti-HVEM scFv induce a potent proliferation and cytokine production of co-cultured T cells. Inoculation of anti-HVEM scFv-expressing tumor results in a spontaneous tumor regression in CD4+ and CD8+ T cell-dependent fashion, associated with the induction of tumor-specific long-term memory. Stimulation of HVEM and 4-1BB co-stimulatory signals by anti-HVEM scFv-expressing tumor vaccine combined with anti-4-1BB mAb shows synergistic effects which achieve regression of pre-established tumor and T cell memory specific to parental tumor. Taken in concert, our data suggest that genetic engineering of tumor cells to selectively potentiate the HVEM signaling pathway is a promising antitumor vaccine therapy.

Spontaneous Complete Regression of Gastric Large-Cell Neuroendocrine Carcinoma: Mediated by Cytomegalovirus-Induced Cross-Autoimmunity?

Spontaneous regression of malignant tumour is a rare phenomenon. This report describes such an occurrence in a gastric large cell neuroendocrine carcinoma of a 77-year-old man. The patient presented with dyspepsia, and biopsy of the fungating mass in the cardia showed a high grade neuroendocrine carcinoma. The pre-operative biopsy taken after 3 months showed chronic inflammation and cytomegalovirus inclusions, but no tumour. In the gastrectomy specimen, no residual tumour was found. Instead, there were foamy histiocytes, chronic inflammatory cells and fibrovascular tissue splitting apart the muscularis propria. In addition, there was ganglionitis involving the myenteric plexus, even in areas of the stomach away from the inflamed site. Chemotherapy, radiotherapy or alternative medicine (including herbal medicine) had not been given. We postulate that cytomegalovirus infection initiated a cross-autoimmune reaction against neuronal cells, and this reaction "unintentionally" eliminated the carcinoma cells which also expressed neural antigens.