Rapid Cancer Progression Research Articles

Renal cell carcinoma with alpha-fetoprotein secretion and tissue expression – A case report

Abstract Introduction Alpha-fetoprotein (AFP) is a glycoprotein which can be elevated in some non-oncological conditions, and in few types of cancers being a diagnostic and monitoring biomarker. Kidney cancer can produce several substances, which have biological activity and even cause paraneoplastic syndromes. AFP elevation in course of renal cancer is extremely rarely encountered. Aim To present diagnostic difficulties in a case of a 43-year-old man with a kidney tumor. Case study Clinical and pathological case description. Results and discussion The patient initially presented with features of urogenital infection and lumbar pain. Performed diagnostics revealed at first epididymitis, then serum elevation of AFP, and finally renal tumor. Based on wide immunophenotyping, the tumor was histopathologically recognized as high grade clear cell renal cell carcinoma with AFP expression. Clinically the patient presented unexpected rapid cancer progression with parallel increase of above biomarker level, causing repeated exclusion assessment of germ cell tumor. Conclusions The diagnostics of kidney mass in our patient was interfered and complicated by concomitant genital infection and AFP serum elevation. Clinically found increased level of AFP requires extensive evaluation, including diagnostics of different tumors.

The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress.

Hypoxia is a major hallmark of the tumor microenvironment that is strictly associated with rapid cancer progression and induction of metastasis. Hypoxia inhibits disulfide bond formation and impairs protein folding in the Endoplasmic Reticulum (ER). The stress in the ER induces the activation of Unfolded Protein Response (UPR) pathways via the induction of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, the level of phosphorylated Eukaryotic Initiation Factor 2 alpha (eIF2α) is markedly elevated, resulting in the promotion of a pro-adaptive signaling pathway by the inhibition of global protein synthesis and selective translation of Activating Transcription Factor 4 (ATF4). On the contrary, during conditions of prolonged ER stress, pro-adaptive responses fail and apoptotic cell death ensues. Interestingly, similar to the activity of the mitochondria, the ER may also directly activate the apoptotic pathway through ER stress-mediated leakage of calcium into the cytoplasm that leads to the activation of death effectors. Apoptotic cell death also ensues by ATF4-CHOP- mediated induction of several pro-apoptotic genes and suppression of the synthesis of anti-apoptotic Bcl-2 proteins. Advancing molecular insight into the transition of tumor cells from adaptation to apoptosis under hypoxia-induced ER stress may provide answers on how to overcome the limitations of current anti-tumor therapies. Targeting components of the UPR pathways may provide more effective elimination of tumor cells and as a result, contribute to the development of more promising anti-tumor therapeutic agents.

Rapid Fatal Progression of Cervical Cancer during Pregnancy Treated by Neoadjuvant Chemotherapy

Cervical cancer is the most commonly diagnosed gynaecological malignancy in pregnant women. The prognosis of this cancer does not seem to be influenced by the pregnancy. However, the cancer management comes into competition with maternal and foetal outcomes, especially during the 2nd trimester of pregnancy. Challenging issues lie in the cervical screening during pregnancy, the evaluation of lymph node status and the indication of neoadjuvant chemotherapy to avoid foetal prematurity without comprising maternal prognosis.

Statewide Retrospective Review of Familial Pancreatic Cancer in Delaware, and Frequency of Genetic Mutations in Pancreatic Cancer Kindreds.

Considering the typical rapid progression and high mortality of pancreatic cancer (PC), early detection may lead to an improved outcome. To date, there is no safe, sensitive, and cost-effective screening strategy to detect PC. Currently, screening is focused on individuals at the highest risk of developing PC based on family history. A high-risk individual is defined as having two or more first-degree relatives with PC, or one first- or second-degree relative with PC with a confirmed mutation in a gene associated with PC. The BRCA2 gene is one of the most common genes linked to pancreatic-only cancer families; however, other hereditary cancer syndromes have also been associated with an increased risk for PC. We conducted a retrospective review of pedigrees of families with a pancreatic adenocarcinoma cancer diagnosis held in the statewide Ruth Ann Minner High Risk Family Cancer Registry at the Helen F. Graham Cancer Center and Research Institute, Christiana Care Health System, Newark, DE, USA, from 2002 to 2013. The registry was queried based on how many first-, second-, or third-degree relatives of the proband were affected with PC, genetic testing status, and (if applicable) the results. These data were then categorized into families that meet familial PC (FPC) criteria, defined as two first-degree relatives with PC (FPC families), families that did not meet the FPC definition but had one first-degree relative affected with PC (first-degree families), and probands with PC (probands). Each family was counted only once in the analysis, even if multiple family members were tested. Our analysis revealed that 175 of 597 families fitting any of the above criteria completed genetic testing. Of this cohort, 52 had pathogenic alterations with nine different genes implicated. Overall, 164 of the 175 families that fitted into any of the three categories previously identified had BRCA1 or BRCA2 testing, either by DNA sequencing or next-generation sequencing via a panel test that included BRCA1/2. BRCA1 pathogenic alterations were noted in 17/164 (10.4%) and BRCA2 pathogenic alterations were noted in 23/164 (14.0%). FPC families (n=46) 42/46 of the FPC families underwent BRCA1/2 testing, and 11/42 (26% [95% CI 12.89-39.49]) had pathogenic alterations. Specifically, 4/42=BRCA1 (9.5%) and 7/42=BRCA2 (16.7%). Additionally, 16/46 of the FPC families underwent exclusively Lynch syndrome (LS) testing, and pathogenic mutations in a mismatch repair protein were identified in 2/16. Specifically, 1/16=MLH1 (6.3%) and 1/16=MSH2 (3.6%). Overall, a genetic mutation within any gene associated with an increased PC risk was found in 28% of FPC families. First-degree families (n=106) 99/106 of the families with one first-degree relative underwent BRCA1/2 testing, and 21/99 (21.2% [95% CI 13.16-29.27]) had pathogenic alterations. Specifically, 11/99=BRCA1 (11.1%) and 10/99=BRCA2 (10.1%). 32/99 first-degree families underwent exclusively LS testing, and pathogenic mutations were identified in 4/32. Specifically, 3/32=MLH1 (9%) and 1/32=MSH6 (3%). 25/99 of the families pursued panel testing, and pathogenic alterations in any gene were identified in 3/25. Specifically, the mutations were found in 1/25=ATM (4%), 1/25=CHEK2 (4%), and 1/25=RAD51D (4%). Affected probands (n=23) Lastly, all 23 probands affected with PC pursued genetic testing. Of these, 11/23 were found to have pathogenic alterations. All 23 underwent BRCA1/2 testing, and pathogenic alterations were identified in 8/23 (35% [95% CI 15.32-54.25]), specifically 2/23=BRCA1 (9%), and 6/23=BRCA2 (26%). 10/23 patients underwent panel testing and pathogenic alterations were found in 3/10 (30%) patients, of whom 1/10=MSH6 (10%), 1/10=ATM (10%), and 1/10=TP53 (10%). This study demonstrates that a statewide high-risk family cancer registry is an important instrument in studying the risk of PC in families. Our analysis revealed 14 mutations associated with FPC, among which hereditary breast and ovarian cancer and LS were most prevalent. BRCA1 was found to have the same association with PC as BRCA2, which appears unique to our population. We plan to use our knowledge of these mutations in developing a PC screening program.

Implementing amplicon-based next generation sequencing in the diagnosis of small cell lung carcinoma metastases

Small cell lung carcinoma (SCLC) is the most aggressive entity of lung cancer. Rapid cancer progression and early formation of systemic metastases drive the deadly outcome of SCLC. Recent advances in identifying oncogenes by cancer whole genome sequencing improved the understanding of SCLC carcinogenesis. However, tumor material is often limited in the clinic. Thus, it is a compulsive issue to improve SCLC diagnostics by combining established immunohistochemistry and next generation sequencing.We implemented amplicon-based next generation deep sequencing in our routine diagnostics pipeline to analyze RB1, TP53, EP300 and CREBBP, frequently mutated in SCLC. Thereby, our pipeline combined routine SCLC histology and identification of somatic mutations. We comprehensively analyzed fifty randomly collected SCLC metastases isolated from trachea and lymph nodes in comparison to specimens derived from primary SCLC.SCLC lymph node metastases showed enhanced proliferation and frequently a collapsed keratin cytoskeleton compared to SCLC metastases isolated from trachea. We identified characteristic synchronous mutations in RB1 and TP53 and non-synchronous CREBBP and EP300 mutations.Our data showed the benefit of implementing deep sequencing into routine diagnostics. We here identify oncogenic drivers and simultaneously gain further insights into SCLC tumor biology.

Comorbid depressive and anxiety disorders in patients with cancer

Patients with cancer face a high risk of comorbid depressive and anxiety disorders that have to be paradigmatically considered within a complex biopsychosocial context. Several conceptual challenges have to be mastered in arriving at a correct clinical diagnosis. Coexistent affective and anxiety disorders in cancer patients include a more dramatic subjective suffering, reduced psychological coping, possible negative interference with somatic treatment and rehabilitation, impaired quality of life and higher grades of psychosocial disability. They may also lead to an overall increased risk of somatic morbidity, a more rapid progression of cancer and a higher cancer-related mortality in the course of the disease. Manifold psychological, psychosocial and existential, cancer and treatment-related stressors have to be considered with respect to common neurobiological, especially neuroendocrine and neuroinflammatory mechanisms. Complex psychosomatic, somatopsychic and somato-somatic effects must always be considered. Evidence-based approaches in psychotherapy and pharmacotherapy exist for the integrative treatment of comorbid depressive and anxiety disorders in cancer.

Interleukin-17 Receptor A Signaling in Transformed Enterocytes Promotes Early Colorectal Tumorigenesis

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine linked to rapid malignant progression of colorectal cancer (CRC) and therapy resistance. IL-17A exerts its pro-tumorigenic activity through its type A receptor (IL-17RA). However, IL-17RA is expressed in many cell types, including hematopoietic, fibroblastoid, and epithelial cells, in the tumor microenvironment, and how IL-17RA engagement promotes colonic tumorigenesis is unknown. Here we show that IL-17RA signals directly within transformed colonic epithelial cells (enterocytes) to promote early tumor development. IL-17RA engagement activates ERK, p38 MAPK, and NF-κB signaling and promotes the proliferation of tumorigenic enterocytes that just lost expression of the APC tumor suppressor. Although IL-17RA signaling also controls the production of IL-6, this mechanism makes only a partial contribution to colonic tumorigenesis. Combined treatment with chemotherapy, which induces IL-17A expression, and an IL-17A neutralizing antibody enhanced the therapeutic responsiveness of established colon tumors. These findings establish IL-17A and IL-17RA as therapeutic targets in colorectal cancer.

Identification and functional validation of RAD23B as a potential protein in human breast cancer progression.

Identification of protein targets that play a role in breast cancer invasion may help to understand the rapid progression of cancer and may lead to the development of new biomarkers for the disease. In this study, we compared two highly invasive and two poorly invasive breast cancer cell lines using comparative label-free LC-MS profiling in order to identify differentially expressed proteins that may be linked to the invasive phenotype in vitro. Forty-five proteins were found to be upregulated, and 34 proteins, downregulated. UV excision repair protein RAD23 homologue B (RAD23B) was found among the downregulated proteins in highly invasive breast cancer cell lines. In poorly invasive breast cancer cell lines, siRNA-mediated downregulation of RAD23B subsequently led to an increase in invasion and adhesion in vitro. Immunohistochemistry analysis of 164 specimens of invasive breast cancer showed that having a high percentage (>80%) of RAD23B positive nuclei was significantly associated with histopathological grades 1 and 2 breast cancer and with low mitotic activity. In addition, a high staining intensity for RAD23B in the cytoplasm was significantly associated with histopathological grade 3 breast cancer. This study suggests a potential role of RAD23B in breast cancer progression and may further imply a tumor suppressor role of nuclear RAD23B in breast cancer.

Treatment with erythropoiesis-stimulating agents in chronic kidney disease patients with cancer

Treatment of anemia remains an important component in the care of patients with nondialysis chronic kidney disease (CKD) and end-stage renal disease (ESRD). Erythropoietin-stimulating agents (ESAs) remains a key anemia treatment strategy in this patient population. However, anemia management in this group can become more complicated by prior or current history of malignancy. There has been a great deal of work both scientifically and in clinical trials in oncology that have revealed certain concerns and risks of ESA use in patients with cancer. In this review, we will bring together knowledge from nephrology and oncology literature to help nephrologists understand the implications for ESA treatment when CKD/ESRD is complicated by cancer. We also suggest an approach to the management of anemia in this patient group with active or previous malignancy.

Initial study of radiological and clinical efficacy radioembolization using 188Re-human serum albumin (HSA) microspheres in patients with progressive, unresectable primary or secondary liver cancers.

BackgroundThe aim of this initial study was to evaluate the clinical and radiological effectiveness of radioembolization (RE) using 188Re-Human Serum Albumin (HSA) microspheres in patients with advanced, progressive, unresectable primary or secondary liver cancers, not suitable to any other form of therapy.Material/MethodsOverall, we included 13 patients with 20 therapy sessions. Clinical and radiological responses were assessed at 6 weeks after therapy, and then every 3 months. The objective radiological response was classified according to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.0 by sequential MRI. Adverse events were evaluated using NCI CTCAE v.4.03.ResultsThere were 4 patients with hepatocellular carcinoma (HCC), 6 with metastatic colorectal cancer (mCRC), 2 with neuroendocrine carcinoma (NEC), and 1 patient with ovarian carcinoma. Mean administered activity of 188Re HSA was 7.24 GBq (range 3.8–12.4) A high microspheres labeling efficacy of over 97±2.1% and low urinary excretion of 188Re (6.5±2.3%) during first 48-h follow-up. Median overall survival (OS) for all patients was 7.1 months (CI 6.2–13.3) and progression-free survival (PFS) was 5.1 months (CI 2.4–9.9). In those patients who had a clinical partial response (PR), stable disease (SD), and disease progression (DP) as assessed 6 weeks after therapy, the median OS was 9/5/4 months, respectively, and PFS was 5/2/0 months, respectively. The treatment adverse events (toxicity) were at an acceptable level. Initially and after 6 weeks, the CTC AE was grade 2, while after 3 months it increased to grade 3 in 4 subjects. This effect was mostly related to rapid cancer progression in this patient subgroup.ConclusionsThe results of this preliminary study indicate that RE using 188Re HSA is feasible and a viable option for palliative therapy in patients with extensive progressive liver cancer. It was well tolerated by most patients, with a low level of toxicity during the 3 months of follow-up.

Rapid progression of second bile duct cancer after resection for extrahepatic bile duct cancer

We report a 77-year-old woman with rapid progression of a second cancer of the remnant distal bile duct after R0 resection for bile duct cancer. Initially, she was referred to us for localized cancer in the mid-area of the common bile duct without pancreaticobiliary maljunction. We performed common bile duct resection and hepaticojejunostomy with lymph node dissection. The tumor was pT1N1M0 by TNM staging. Six months later, CT newly revealed a mass in the residual distal bile duct. Endoscopic retrograde cholangiography showed an elevated tumor near the distal bile duct’s upper edge and a well-defined tumor in the inferior part of the distal bile duct. Subtotal stomach-preserving pancreatoduodenectomy was performed 8 months after the first operation. Postoperative pathological examination of both lesions indicated well-differentiated adenocarcinoma. No continuation was noted between the two cancers in the mucosal or subepithelial layer. Repeated surgical resection resulted in a pathologically curative treatment.

Sensitive and Specific Antibody Probes Directed Against The Erythropoietin Receptor – From Basic Studies To Clinical Implementation

Recombinant erythropoietin (Epo) is an effective anti-anemic agent in most cancer patients and improves their quality of life. Yet, concerns of disease progression and reduced survival in recombinant human Epo (rhuEpo)-treated patients have been raised by Phase III clinical trial data showing more rapid cancer progression and reduced survival in subjects randomized to Epo. Epo has pleiotropic actions and its receptor, EpoR, is expressed by many different cell types outside the erythroid compartment. It was thus proposed that a major possible mechanism for this potentially harmful effect of Epo in cancer patients is the activation of EpoRs on cancer cells. The original clinical studies have been criticized because they deployed polyclonal antibodies later shown to lack specificity for EpoR.Furthermore, multiple isoforms of EpoR caused by differential splicing have been reported, but only at the RNA level, in different cancer cell lines. Investigations into whether these spliced versions actually result in abnormal EpoR forms at the protein level, alter Epo responsiveness and have an impact on tumor progression in vivo, have been hampered by a lack of well characterized monoclonal antibodies.The ‘EpoCan' Consortium, funded by the EU, is directed to promote improved pathological testing of EpoR in patient samples, leading to safer clinical use of rHuEpo and other Erythropoietic Stimulating Agents (ESAs). To date, 25 murine and rat monoclonal antibodies have been produced against the EpoR, using novel genetic and traditional peptide immunization protocols. Of these antibodies, several were found to specifically recognize the receptor in various assays including Western blot (WB), immunoprecipitation (IP), immunofluorescence (IF), flow cytometry (FACS) and immunohistochemistry (IHC). Table 1 lists the antibodies that were selected for further analysis, and their experimental applications. The antibodies were tested on EpoR transfected cells (HEK 293 cells and COS cells) and Epo-dependent UT7 cells which endogenously express EpoR. In addition the antibodies were tested on non-erythroid cells viz. the non-small cell lung carcinoma A549, and breast cancer MDA-MB 231 cell lines. Specificity of the antibodies towards the EpoR in these two latter cell lines was ensured by the lack of reactivity with the corresponding EpoR silenced cells.Table 1Anti EpoR Antibodies - immunizing antigens and applicationsImmunogenSubclone nameSystematic nameIsotypeEpitope locationApplicationsPeptideBCO-3H2-D3GM1201rIgG2bhEpoR cytoplasmic domainWB, IP, IF, IHCPeptideBCO-4B5-C9GM1202rIgG2ah/mEpoR cytoplasmic domainWB, IF, IHCDNAVP-2E8-B6GM1204mIgG1hEpoR extracellular domainIP, IF, FACSDNAVP-4D8-C4GM1205mIgG1hEpoR extracellular domainIP, IF, FACSDNABBQ-9C4-D8GM1206rIgG2ah/mEpoR extracellular domainFACSDNABBQ-10E10-F2GM1207rIgG2ah/mEpoR extracellular domainWBImmunohistochemical analysis was performed on a panel of human non-small cell lung carcinoma sections. Two rat monoclonal antibodies, BCO-3H2-D3 which recognizes full length EpoR and BCO-4B5-C9 which recognizes full length and truncated isoforms, have proved valuable in comparative immunohistochemical and Western blot studies in a range of human tumors and cell lines. These well characterized monoclonal antibodies will enable a careful dissection of EpoR function in cancer cells and the detection of EpoR isoforms in tumor tissue.In the longer term such studies should allow clinicians to balance the benefits and risks of ESA treatment in cancer.THIS WORK WAS SUPPORTED BY THE FP7-HEALTH EUROPEAN COMMISSION EPOCAN GRANT (282551). Disclosures:Grunert:Aldevron Freiburg GmBH: Employment. Thompson:Aldevron Freiburg GmbH: Employment.

An interdisciplinary model for predicting patients at high risk for readmission amongst solid tumor oncology patients in a comprehensive cancer center.

190 Background: Increasing emphasis is being placed on reducing hospital readmission (readm) rates. Reduction of hospital readm remains a challenge, especially among the oncology population. Identifying patients (pts) at increased risk can assist with developing targeted interventions. Methods: From 1/1/11 to 12/31/12, an interdisciplinary team consisting of medical oncologists, hospitalist physician and NP, QI specialist, and case manager prospectively reviewed the medical oncology inpatient census on a biweekly basis to identify pts at risk for readm. Pts with any of the following conditions were considered at high risk for readm: significant pain, wounds, intestinal obstruction, refractory neutropenia despite GCSF, elderly/frail, unstable housing, patient/family non-compliance, rapid cancer progression, refusal of appropriate hospice care, and stalled care plans. These criteria were based upon previous years’ anecdotal experience. Interdisciplinary interventions to address these conditions were identified and initiated. Results: 272 pts were assessed during these sessions. Each session took on average 60 minutes. 69 pts (25%) were deemed to have at least one high risk factor. Chart review revealed that 6 died in the hospital and 13 were discharged to hospice. No pts on hospice were readmitted. Of the remaining 50 high risk pts, 14 (28%) and 25 (50%) pts were readmitted within 14 days and 30 days, respectively. Conclusions: This interdisciplinary team model seems to have a fair predictive value in identifying pts at higher risk for readmission. However, it is time and labor intensive. Enrollment of appropriate high risk pts in hospice mitigates this risk. Given the current emphasis on decreasing readm and the increased cost/penalties associated with readm, the next step will be to pilot cost-effective interventions for pts with these high risk factors. Potential interventions which we have instituted include follow-up calls, social service referrals, intensive family/pt education, clinic appointments within 3 days of discharge, greater coordination with primary care physicians, and more effective hospice discussions. Supported by CA 62505.

Bedtime misalignment and progression of breast cancer

Disruption of circadian rhythms, which frequently occurs during night shift work, may be associated with cancer progression. The effect of chronotype (preference for behaviors such as sleep, work, or exercise to occur at particular times of day, with an associated difference in circadian physiology) and alignment of bedtime (preferred vs. habitual), however, have not yet been studied in the context of cancer progression in women with breast cancer. Chronotype and alignment of actual bedtime with preferred chronotype were examined using the Morningness–Eveningness Scale (MEQ) and sleep-wake log among 85 women with metastatic breast cancer. Their association with disease-free interval (DFI) was retrospectively examined using the Cox proportional hazards model. Median DFI was 81.9 months for women with aligned bedtimes (“going to bed at preferred bedtime”) (n = 72), and 46.9 months for women with misaligned bedtimes (“going to bed later or earlier than the preferred bedtime”) (n = 13) (log rank p = 0.001). In a multivariate Cox proportional hazard model, after controlling for other significant predictors of DFI, including chronotype (morning type/longer DFI; HR = 0.539, 95% CI = 0.320–0.906, p = 0.021), estrogen receptor (ER) status at initial diagnosis (negative/shorter DFI; HR = 2.169, 95% CI = 1.124–4.187, p = 0.028) and level of natural-killer cell count (lower levels/shorter DFI; HR = 1.641, 95% CI = 1.000–2.695, p = 0.050), misaligned bedtimes was associated with shorter DFI, compared to aligned bedtimes (HR = 3.180, 95% CI = 1.327–7.616, p = 0.018). Our data indicate that a misalignment of bedtime on a daily basis, an indication of circadian disruption, is associated with more rapid breast cancer progression as measured by DFI. Considering the limitations of small sample size and study design, a prospective study with a larger sample is necessary to explore their causal relationship and underlying mechanisms.

Minding the body: Psychotherapy and cancer survival

This article reviews evidence regarding effects of psychotherapy on overall cancer survival time. Special emphasis is given to research on adverse effects of depression on cancer survival, breast cancer, and mediating psychophysiological pathways linking psychosocial support to longer survival. It reviews all published clinical trials addressing effects of psychotherapy on cancer survival, emphasizing depression, breast cancer, and psychophysiological evidence linking stress, depression, and support to cancer survival. Systematic literature review and synthesis. Eight of 15 published trials indicate that psychotherapy enhances cancer survival time. No studies show an adverse effect of psychotherapy on cancer survival. Potential psychophysiological mechanisms linking stress to shorter survival include dysregulation of diurnal cortisol, increased pro-inflammatory cytokines, reduced natural killer cell activity, shorter telomeres and lower telomerase activity, glucocorticoid-mediated suppression of p53 and BrCA1 gene expression, and sympathetic nervous system activation of vascular endothelial growth factor. Stress and support affect the course of cancer progression. What is known? Stress and support have been thought to be related to cancer risk and progression, but evidence has been mixed. Depression is a natural co-morbid condition with cancer. It has not been clear how stress and support could physiologically affect the rate of cancer progression. Immune function was not thought to have much relevance to cancer progression. Few other physiological mechanisms linking stress to cancer progression were known. What does this paper add? There is evidence from 15 RCTs indicating that effective psychosocial support improves quantity as well as quality of life with cancer. There is evidence that chronic depression predicts poorer prognosis with cancer. Dysregulated circadian cortisol patterns predict more rapid cancer progression. Inflammatory processes affect cancer growth and progression. Sympathetic nervous system activity, telomere length, telomerase activity, and oncogene expression are affected by stress and can affect cancer growth.

Methotrexate therapy leading to a rapid progression of a previously indolent prostate cancer: Is immunosuppression to blame?

Methotrexate therapy has been associated with occurrence and/or accelerated progression of malignancies. We describe a patient who developed widespread bone metastases of a previously confined to the prostate gland prostate cancer shortly after starting methotrexate therapy for rheumatoid arthritis and large granular lymphocyte leukemia. We believe an immunosuppressive milieu brought on by the methotrexate use in this case is responsible for the rapid progression of prostate cancer leading to the patient's demise. To the best of our knowledge, no association has been made to date between the therapy with methotrexate and a fulminant course of a previously indolent prostate cancer. Given its utilization in a variety of benign and malignant conditions and the ageing population, caution is advised with the use of this agent, especially in the presence of an underlying malignancy.

Abstract 1627: Fibroblast HGF elicits c-MET-mediated signaling and migration in ovarian cancer cells.

Abstract Background: Epithelial ovarian cancer (EOC) has the highest mortality rate of all gynecologic malignancies diagnosed in the U.S. due to its rapid progression without symptom. Stromal components in the ovary contribute to rapid progression of cancer and interruption of their interaction with cancer cells are being explored as important therapeutic target. Hepatocyte growth factor (HGF) is expressed primarily in mesenchymal cells and acts on epithelial cells. HGF is also a unique cytokine that induces pleiotropic biological responses, involving proliferation, invasion, and dissemination of cancer cells. We studied c-MET/HGF axis as a mediator of tumor-stromal interactions in ovarian cancer using human ovarian fibroblast and their derived extracellular matrices (ECM). Methods: Six EOC cells were each cultured alone or in the presence of three human ovarian fibroblast cultures and their derived ECM in Transwell plates and the number of migrated cells was quantitated. ELISA was used to measure the concentration of HGF secreted by cancer cells and fibroblasts or released from fibroblast-derived ECM. EOC cells were treated with conditioned media derived from fibroblast that secretes high level of HGF and c-MET mediated signalling was assessed by immunoblotting. Results: Five out of the six EOC cells tested highly expressed c-MET and none produced detectable levels of HGF. IHFNO-303, a human ovarian fibroblast line, secreted the highest level of HGF (∼3,800 pg/mL) and markedly enhanced migration (2 to 140-fold increase) of the EOC cells that express c-MET. Recombinant HGF and a HGF neutralizing antibody were used to validate HGF as a major migratory factor secreted by fibroblast. HGF sequestered within the fibroblast-derived ECM was also able to stimulate cell migration by 1.5 to 24-fold, when released via EOC-associated degradation of the ECM. In cells containing constitutive c-MET phosphorylation, recombinant HGF and fibroblast-derived HGF negligibly affect c-MET phosphorylation on Tyr1234 and Tyr1003. However, both sources of HGF increased the phosphorylation of c-MET on Tyr1349, the multisubstrate docking site, by more than 6-fold and led to activation of downstream signalling transducers, e.g., AKT and ERK, in all c-MET expressing EOC cells. Therefore, signalling mediated by c-MET and HGF likely occurs in a paracrine manner in ovarian cancer. Conclusion: Our study demonstrates the functional contribution of c-MET and HGF signalling in malignant progression driven by important tumor-stromal interactions. We demonstrate for the first time that phosphorylation of c-MET on Tyr1349 requires extraneous HGF and phosphorylated c-MET level on Try1349 might be a good indicator of c-MET activation in the microenvironment and likely responsive to c-MET targeted therapy. Citation Format: Youngjoo Kwon, Yan Zhou, Andrew K. Godwin. Fibroblast HGF elicits c-MET-mediated signaling and migration in ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1627. doi:10.1158/1538-7445.AM2013-1627

Activation of the unfolded protein response bypasses trastuzumab-mediated inhibition of the PI-3K pathway

HER2-positive breast cancer initially responds to trastuzumab treatment, but over time, resistance develops and rapid cancer progression occurs, for which various explanations have been proposed. Here we tested the hypothesis that induction of the unfolded protein response (UPR) could override HER2 inhibition by trastuzumab, leading to the re-activation of growth signaling and the activation of the downstream target Lipocalin 2 (LCN2). Trastuzumab significantly inhibited the basal expression of LCN2 in HER2 + SKBr3 human breast cancer cells. The induction of the UPR completely abrogated trastuzumab-mediated LCN2 downregulation, and, in fact caused an increase in transcription and secretion of LCN2 over baseline. Reduction of the UPR using 4-phenyl butyric acid (PBA) a chemical chaperone that ameliorates ER stress, restored trastuzumab-mediated inhibition. Inhibition of the PI3K/AKT signaling pathway in trastuzumab-treated/UPR-induced SKBr3 cells partially reduced the upregulation of LCN2. These results suggest that the UPR is a possible way to override the effect of trastuzumab in HER2+ cancer cells.

Risk factors for skin cancer development in patients after organ transplantation

Cancer has become the second most common cause of death in patients after organ transplantation. Among all cancers arising de novo after transplantation skin cancers are the most common, accounting for 95% of all skin neoplasms. Due to the significantly higher morbidity, aggressive, rapid progression of cancer and unfavorable prognosis, the population requires a specific oncological approach. Therefore, special attention should be paid to factors predisposing to the development of cancer, including skin cancer, in patients after organ transplantation. Some of these factors are well understood, while the role of others is still ambiguous. Among the etiological factors mentioned are those that are associated with the recipient. These include genetic factors such as male sex, fair skin and inability to be tanned, and compatibility of the HLA system, and non genetic factors such as patient age, chronic skin ulcers and scars, the type of transplanted organ, immunosuppression, and particularly the type and cumulative doses of drugs. In addition, the pathogenesis of cancer is influenced by environmental factors such as exposure to sunlight and therefore latitude, ionizing radiation, chemical carcinogens and viral infections. Knowledge of etiological factors and mechanisms of etiopathogenesis allow for indication and observation of patients with increased risk of cancer as well as faster healing in these patients.

Calcineurin Inhibitor-Induced and Ras-Mediated Overexpression of VEGF in Renal Cancer Cells Involves mTOR through the Regulation of PRAS40

Malignancy is a major problem in patients treated with immunosuppressive agents. We have demonstrated that treatment with calcineurin inhibitors (CNIs) can induce the activation of proto-oncogenic Ras, and may promote a rapid progression of human renal cancer through the overexpression of vascular endothelial growth factor (VEGF). Interestingly, we found that CNI-induced VEGF overexpression and cancer cell proliferation was inhibited by rapamycin treatment, indicating potential involvement of the mammalian target of rapamycin (mTOR) pathway in this tumorigenic process. Here, we examined the role of mTOR pathway in mediating CNI- and Ras-induced overexpression of VEGF in human renal cancer cells (786-0 and Caki-1). We found that the knockdown of raptor (using siRNA) significantly decreased CNI-induced VEGF promoter activity as observed by promoter-luciferase assay, suggesting the role of mTOR complex1 (mTORC1) in CNI-induced VEGF transcription. It is known that mTOR becomes activated following phosphorylation of its negative regulator PRAS40, which is a part of mTORC1. We observed that CNI treatment and activation of H-Ras (through transfection of an active H-Ras plasmid) markedly increased the phosphorylation of PRAS40, and the transfection of cells using a dominant-negative plasmid of Ras, significantly decreased PRAS40 phosphorylation. Protein kinase C (PKC)-ζ and PKC-δ, which are critical intermediary signaling molecules for CNI-induced tumorigenic pathway, formed complex with PRAS40; and we found that the CNI treatment increased the complex formation between PRAS40 and PKC, particularly (PKC)-ζ. Inhibition of PKC activity using pharmacological inhibitor markedly decreased H-Ras-induced phosphorylation of PRAS40. The overexpression of PRAS40 in renal cancer cells significantly down-regulated CNI- and H-Ras-induced VEGF transcriptional activation. Finally, it was observed that CNI treatment increased the expression of phosho-PRAS40 in renal tumor tissues in vivo. Together, the phosphorylation of PRAS40 is critical for the activation of mTOR in CNI-induced VEGF overexpression and renal cancer progression.