Genetic variants in IL12 influence both hepatitis B virus clearance and HBV-related hepatocellular carcinoma development in a Chinese male population

Abstract

IL12 plays a major role not only in inducing appropriate immune responses against viral infections (including HBV) but also in the antitumor immune response. This study was conducted to investigate the relationships of genetic variants in IL12 with hepatitis B virus (HBV) clearance and development of HBV-related hepatocellular carcinoma (HCC). We genotyped three single nucleotide polymorphisms (SNPs) of the IL12A (rs568406 and rs2243115) and IL12B (rs3212227) in 395 HBV-positive HCC patients, 293 persistent HBV carriers and 686 subjects with HBV natural clearance from southern China, using the improved multiplex ligase detection reaction (iMLDR) method. Logistic regression analysis adjusted for age, smoking, and alcohol consumption status showed that rs568408 variant genotypes were significantly associated with host HBV-related HCC risk when compared with persistent HBV carriers, and carriers of the GA + AA genotype decreased the HCC risk in comparison with GG carriers (adjusted OR = 0.53, 95 % CI 0.35–0.80, P = 0.002). No relationships between the rs2243115 and rs3212227 SNPs and HCC risk were observed (all P > 0.05). Besides, rs568408 showed an approaching significant effect on susceptibility to HBV persistent infection (adjusted OR = 1.34, 95 % CI 0.99–1.81, P = 0.057 in dominant genetic models). Furthermore, the TG haplotype was observed to be associated with a significantly increased risk of HBV-related HCC (OR = 1.42, 95 % CI 1.10–1.83, P = 0.006), while TA haplotype was associated with a decreased risk of HBV-related HCC (OR = 0.61, 95 % CI 0.45–0.83, P = 0.002). Our results reveal that the IL12A rs568408 variant may be a marker SNP for risk of both HBV clearance and HBV-related HCC development.

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Inhibitory effects of Arhgap6 on cervical carcinoma cells

Abstract

Ras homology GTPase activation protein 6 (Arhgap6), as a member of the rhoGAP family of proteins, performs vital functions on the regulation of actin polymerization at the plasma membrane during several cellular processes. The role of Arhgap6 in the progression and development of cancer remains nearly unknown. This study aimed at exploring the effects of Arhgap6 on cervical carcinoma. Human cervical cancer cells HeLa and SiHa were transduced with a lentivirus targeting Arhgap6 (Arhgap6+), while CaSki and C4-1 cells were transfected with miRNA. Cell proliferation was identified by Cell Counting Kit-8 (CCK-8). Cell cycle distribution and cell apoptosis were identified by flow cytometry. The capacity of cell migration, invasion, and adhesion were detected by Transwell assay. Further, quantitative real-time PCR (qRT-PCR) and western blot were used to analyze the expression levels of Arhgap6 and several tumor-related genes. Co-immunoprecipitation assay was performed to validate the interaction between Arhgap6 and Rac3 (Ras-related C3 botulinum toxin substrate 3). Results showed that Arhgap6 inhibited cell proliferation, migration, invasion, and adhesion of cervical carcinoma, induced cell apoptosis, and caused cell cycle arrest in the G0/G1 phase (n = 3, p < 0.05). Expression of the tumor suppressor genes and oncogenes were up- and down-regulated respectively by Arhgap6, and Rac3 was proved to be the target of Arhgap6. Besides, in in vivo assays, tumor size and weight were destructed in Arhgap6+ athymic nude mouse. This study indicated that Arhgap6 may play a role in the treatment of cervical cancer as a tumor supressor.

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Assessing cancer-related distress in cancer patients and caregivers receiving outpatient psycho-oncological counseling

Abstract

Purpose

The diagnosis of cancer, the symptoms of the illness and its treatment have an influence on how patients and their caregivers experience distress. However, data focusing on caregivers and their cancer-related distress in the outpatient setting is sparse. This study aimed to compare cancer-related distress of caregivers and patients and to derive implications for the system of outpatient psycho-oncological care.

Methods

One hundred thirty-eight patients and 102 caregivers receiving psycho-oncological counseling completed a standardized interview based on a self-assessment questionnaire (Questionnaire on Stress in Cancer Patients, FBK).

Results

Group comparisons for cancer-related distress revealed one statistically significant difference for the subscale ‘Fear’ of the FBK, Z = 2.308, p = .021, and d = .44. Caregivers showed higher cancer-related fear (M = 2.76, SD = 1.14) than patients (M = 2.41, SD = 1.29). There were no differences in ‘psychosomatic complaints’, ‘information deficit’, ‘restrictions in everyday life’, ‘social strains’, or the total score of the FBK.

Conclusions

Caregivers seem to experience cancer-related distress equal to or even more severely than patients themselves. Results suggest that there is a need for more low-threshold offers of outpatient psycho-oncological counseling for caregivers.

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Developing and implementing a complex Complementary and Alternative (CAM) nursing intervention for breast and gynecologic cancer patients undergoing chemotherapy—report from the CONGO (complementary nursing in gynecologic oncology) study

Abstract

Purpose/objectives

The purpose of this study was to develop a complex nursing intervention including complementary and alternative medicine (CAM) for breast and gynecologic cancer patients during chemotherapy to improve quality of life.

Methods

Data sources Theoretical framework and concepts, practical nursing knowledge, and evidence-based studies were compiled in interprofessional meetings.

Data synthesis The final complex intervention consists of three autonomous, but interacting components: (1) CAM nursing package, (2) resource-oriented counseling, and (3) evidence-based information material on CAM. CAM interventions include acupressure, aromatherapy, compress, and massage, targeting 14 clinically relevant symptoms during chemotherapy. Participants receive these interventions during chemotherapy with instructions for self care. During a counseling interview, the patient’s needs and preferences are assessed by trained nurses. Furthermore, participants are equipped with evidence-based information material (booklet and DVD). Prior to study start, nurses attended training modules for administering CAM therapies and for communicating and counseling within the salutogenic approach.

Conclusions

It was possible to design a multimodal CAM nursing intervention based on a theoretical concept, evidence-based studies, and practical nursing experience targeting the prevention or relief of side-effects women suffer during chemotherapy. The systematic analysis of the CONGO study will contribute to evidence-based CAM nursing care within supportive cancer care.

Implications for integrative cancer care

Oncology nurses play an important role in supportive CAM care of breast and gynecologic cancer patients in daily clinical practice. Within oncology outpatient services, the implementation of evidence-based CAM nursing interventions and counseling may contribute to understand the impact of nursing on patient quality of life and symptom relief. This can lead to a new understanding of the nurse’s professional role.

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Penfluridol: An antipsychotic agent suppresses metastatic tumor growth in triple negative breast cancer by inhibiting integrin signaling axis

Metastasis of breast cancer, especially to the brain, is the major cause of mortality. The inability of anti-cancer agents to cross the blood-brain-barrier represents a critical challenge for successful treatment. In the current study, we investigated the anti-metastatic potential of penfluridol (PF), an antipsychotic drug frequently prescribed for schizophrenia with anti-cancer activity. We show that PF induced apoptosis and reduced the survival of several metastatic triple negative breast cancer (TNBC) cell lines. Additionally, PF treatment significantly reduced the expression of integrinα6, integrin β4, Fak, Paxillin, Rac1/2/3, and ROCK1 in vitro. We further evaluated the efficacy of PF in three different in vivo tumor models. We demonstrate that PF administration to an orthotopic model of breast cancer suppressed tumor growth by 49%. On the other hand, PF treatment inhibited the growth of metastatic brain tumors introduced by intracardiac or intracranial injection of breast cancer cells by 90% and 72%, respectively. PF-treated tumors from all three models exhibited reduced integrinβ4 and increased apoptosis. Moreover, chronic administration of PF failed to elicit significant toxic or behavioral side effects in mice. Taken together, our result indicate that PF effectively reduces the growth of primary TNBC tumors and especially metastatic growth in the brain by inhibiting integrin signaling, and prompt further preclinical investigation into repurposing PF for the treatment of metastatic TNBC.

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The CDK9 inhibitor dinaciclib exerts potent apoptotic and antitumor effects in preclinical models of MLL-rearranged acute myeloid leukemia

Translocations of the mixed lineage leukemia (MLL) gene occur in 60-80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDACs), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate protumorigenic gene expression programs. We conducted a small molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven AML. We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the pro-survival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclib-induced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies, and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins.

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Melphalan, Antimelanoma Immunity, and Inflammation—Letter

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Dependence Receptor and Cancer

Data accumulating over the last 20 years support the notion that some transmembrane receptors are activated not only by their respective ligands but also, differentially, by the withdrawal or absence of these same ligands. In this latter setting, these receptors actively trigger apoptosis. They have been dubbed dependence receptors because their expression confers a state of ligand dependence for survival on the expressing cells. Twenty of these receptors have been identified to date, and several have been shown to inhibit tumor progression by inducing apoptosis. As a corollary, these receptors, or their transduced death signals, are frequently silenced in cancer cells as a selective mechanism to prevent cell death, allowing invasion and metastasis. Drugs aimed at inducing programmed cell death in neoplastic cells by re-engaging the proapoptotic activity induced by unliganded dependence receptors are in late-stage preclinical tests, poised for clinical evaluation. This approach may offer novel opportunities for patient treatments. In this review, we discuss the implications of dependence receptors in limiting cancer progression and address the therapeutic perspectives brought to light by this paradigm. Cancer Res; 75(24); 1–5. ©2015 AACR.

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Cancer Education

Modern cancer therapy/care involves the integration of basic, clinical, and population-based research professionals using state-of-the-art science to achieve the best possible patient outcomes. A well-integrated team of basic, clinical, and population science professionals and educators working with a fully engaged group of creative junior investigators and trainees provides a structure to achieve these common goals. To this end, the structure provided by cancer-focused educational programs can create the integrated culture of academic medicine needed to reduce the burden of cancer on society. This summary outlines fundamental principles and potential best practice strategies for the development of integrated educational programs directed at achieving a work force of professionals that broadly appreciate the principals of academic medicine spanning the breadth of knowledge necessary to advance the goal of improving the current practice of cancer care medicine. Cancer Res; 75(24); 1–4. ©2015 AACR.

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Druggable Mutations in Childhood Cancer

Despite improvements in survival rates for children with cancer since the 1960s, progress for many pediatric malignancies has slowed over the past two decades. With the recent advances in our understanding of the genomic landscape of pediatric cancer, there is now enthusiasm for individualized cancer therapy based on genomic profiling of patients' tumors. However, several obstacles to effective personalized cancer therapy remain. For example, relatively little data from prospective clinical trials demonstrate the selective efficacy of molecular-targeted therapeutics based on somatic mutations in the patient's tumor. In this commentary, we discuss recent advances in preclinical testing for pediatric cancer and provide recommendations for providing scientific justification and translational relevance for novel therapeutic combinations for childhood cancer. Establishing rigorous criteria for defining and validating druggable mutations will be essential for the success of ongoing and future clinical genomic trials for pediatric malignancies. Cancer Res; 75(24); 1–11. ©2015 AACR.

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Comprehensive Phenotyping of Rare PIK3CA Variants

Large-scale sequencing efforts are uncovering the complexity of cancer genomes, which are composed of causal “driver” mutations that promote tumor progression along with many more pathologically neutral “passenger” events. The majority of mutations, both in known cancer drivers and uncharacterized genes, are generally of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers. Here we describe a mutation assessment pipeline enabled by high-throughput engineering of molecularly barcoded gene variant expression clones identified by tumor sequencing. We first used this platform to functionally assess tail mutations observed in PIK3CA, which encodes the catalytic subunit alpha of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) frequently mutated in cancer. Orthogonal screening for PIK3CA variant activity using in vitro and in vivo cell growth and transformation assays differentiated driver from passenger mutations, revealing that PIK3CA variant activity correlates imperfectly with its mutation frequency across breast cancer populations. Although PIK3CA mutations with frequencies above 5% were significantly more oncogenic than wild-type in all assays, mutations occurring at 0.07% to 5.0% included those with and without oncogenic activities that ranged from weak to strong in at least one assay. Proteomic profiling coupled with therapeutic sensitivity assays on PIK3CA variant-expressing cell models revealed variant-specific activation of PI3K signaling as well as other pathways that include the MEK1/2 module of mitogen-activated protein kinase pathway. Our data indicate that cancer treatments will need to increasingly consider the functional relevance of specific mutations in driver genes rather than considering all mutations in drivers as equivalent. Cancer Res; 75(24); 1–14. ©2015 AACR.

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IL15 in T-cell Therapy of Cancer

Preclinical models revealed that the immune system can mediate rejection of established tumors, but direct evidence in humans has been limited to largely immunogenic tumors, such as melanoma. The recent success of immune checkpoint inhibitors and adoptive T-cell transfer immunotherapy in clinical trials has instilled new hope for the use of T-cell immunotherapy in the treatment of cancer. IL15, a potent immunostimulatory cytokine, both potentiates host T-cells and natural killer (NK) cell immune responses and promotes the generation of long-lived memory T cells with superior functional capacity, with potential use in adoptive T-cell transfer protocols. IL15 has been recently tested in the clinic and showed dramatic effects at the level of responding NK and CD8+ memory T cells. The recent advances in the knowledge of IL15-dependent regulation of T-cell responses, gene expression, and metabolic adaptation have important implications for the use of IL15 in T-cell–based immunotherapy of cancer. Cancer Res; 75(24); 1–7. ©2015 AACR.

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Genomic Profiling of Merkel Cell Carcinomas

Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors; however, viral-negative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viral-negative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (n = 13) and -negative (n = 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or amplified cancer genes of potential clinical importance included PI3K (PIK3CA, AKT1, PIK3CG) and MAPK (HRAS, NF1) pathway members and the receptor tyrosine kinase FGFR2. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell–infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities. Cancer Res; 75(24); 1–7. ©2015 AACR.

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Melphalan, Antimelanoma Immunity, and Inflammation—Response

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Amphiregulin is a critical downstream effector of estrogen signaling in ERAlpha-positive breast cancer

Estrogen stimulation promotes epithelial cell proliferation in estrogen receptor (ERAlpha)-positive breast cancer. Many ERAlpha target genes have been enumerated, but the identities of the key effectors mediating the estrogen signal remain obscure. During mouse mammary gland development, the EGF eceptor ligand amphiregulin acts as an important stage-specific effector of estrogen signaling. In this study, we investigated the role of amphiregulin in breast cancer cell proliferation using human tissue samples and tumor xenografts in mice. Amphiregulin was enriched in ERAlpha-positive human breast tumor cells and required for estrogen-dependent growth of MCF7 tumor xenografts. Further, amphiregulin levels were suppressed in patients treated with endocrine therapy. Suppression of EGF receptor signaling appeared necessary for the amphiregulin response in this setting. Our findings implicate amphiregulin as a critical mediator of the estrogen response in ERAlpha-positive breast cancer, emphasizing the importance of EGF receptor signaling in breast tumor pathogenesis and therapeutic response.

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uPAR Promotes Skin Tumor Formation

The urokinase-type plasminogen activator receptor (uPAR) has a well-established role in cancer progression, but it has been little studied at earlier stages of cancer initiation. Here, we show that uPAR deficiency in the mouse dramatically reduces susceptibility to the classical two-stage protocol of inflammatory skin carcinogenesis. uPAR genetic deficiency decreased papilloma formation and accelerated keratinocyte differentiation, effects mediated by Notch1 hyperactivation. Notably, Notch1 inhibition in uPAR-deficient mice rescued their susceptibility to skin carcinogenesis. Clinically, we found that human differentiated keratoacanthomas expressed low levels of uPAR and high levels of activated Notch1, with opposite effects in proliferating tumors, confirming the relevance of the observations in mice. Furthermore, we found that TACE-dependent activation of Notch1 in basal kerantinocytes was modulated by uPAR. Mechanistically, uPAR sequestered TACE within lipid rafts to prevent Notch1 activation, thereby promoting cell proliferation and tumor formation. Given that uPAR signaling is nonessential for normal epidermal homeostasis, our results argue that uPAR may present a promising disease-specific target for preventing skin cancer development. Cancer Res; 75(22); 1–15. ©2015 AACR.

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Evolution and Cancer Treatment

The dynamic cancer ecosystem, with its rich temporal and spatial diversity in environmental conditions and heritable cell phenotypes, is remarkably robust to therapeutic perturbations. Even when response to therapy is clinically complete, adaptive tumor strategies almost inevitably emerge and the tumor returns. Although evolution of resistance remains the proximate cause of death in most cancer patients, a recent analysis found that evolutionary terms were included in less than 1% of articles on the cancer treatment outcomes, and this has not changed in 30 years. Here, we review treatment methods that attempt to understand and exploit intratumoral evolution to prolong response to therapy. In general, we find that treating metastatic (i.e., noncurable) cancers using the traditional strategy aimed at killing the maximum number of tumor cells is evolutionarily unsound because, by eliminating all treatment-sensitive cells, it enables rapid proliferation of resistant populations—a well-known evolutionary phenomenon termed “competitive release.” Alternative strategies, such as adaptive therapy, “ersatzdroges,” and double-bind treatments, shift focus from eliminating tumor cells to evolution-based methods that suppress growth of resistant populations to maintain long-term control. Cancer Res; 75(22); 1–6. ©2015 AACR.

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Nrf2 and Skin Cancer

Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical relevance of our findings, we confirm that NRF2 and protumorigenic NRF2 target genes were activated in some actinic keratoses, the major precancerous lesion in human skin. Overall, our results reveal an unexpected tumor-promoting activity of activated NRF2 during early phases of skin tumorigenesis. Cancer Res; 75(22); 1–13. ©2015 AACR.

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Tumor Microenvironment Confers De Novo Therapy Resistance

Resistance to currently available targeted therapies significantly hampers the survival of patients with prostate cancer with bone metastasis. Here we demonstrate an important resistance mechanism initiated from tumor-induced bone. Studies using an osteogenic patient-derived xenograft, MDA-PCa-118b, revealed that tumor cells resistant to cabozantinib, a Met and VEGFR-2 inhibitor, reside in a “resistance niche” adjacent to prostate cancer-induced bone. We performed secretome analysis of the conditioned medium from tumor-induced bone to identify proteins (termed “osteocrines”) found within this resistance niche. In accordance with previous reports demonstrating that activation of integrin signaling pathways confers therapeutic resistance, 27 of the 90 osteocrines identified were integrin ligands. We found that following cabozantinib treatment, only tumor cells positioned adjacent to the newly formed woven bone remained viable and expressed high levels of pFAK-Y397 and pTalin-S425, mediators of integrin signaling. Accordingly, treatment of C4-2B4 cells with integrin ligands resulted in increased pFAK-Y397 expression and cell survival, whereas targeting integrins with FAK inhibitors PF-562271 or defactinib inhibited FAK phosphorylation and reduced the survival of PC3-mm2 cells. Moreover, treatment of MDA-PCa-118b tumors with PF-562271 led to decreased tumor growth, irrespective of initial tumor size. Finally, we show that upon treatment cessation, the combination of PF-562271 and cabozantinib delayed tumor recurrence in contrast to cabozantinib treatment alone. Our studies suggest that identifying paracrine de novo resistance mechanisms may significantly contribute to the generation of a broader set of potent therapeutic tools that act combinatorially to inhibit metastatic prostate cancer. Cancer Res; 75(22); 1–11. ©2015 AACR.

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MUC16 and Cancer Therapeutics

CA125, the most widely used ovarian cancer biomarker, was first identified approximately 35 years ago in an antibody screen against ovarian cancer antigen. Two decades later, it was cloned and characterized to be a transmembrane mucin, MUC16. Since then, several studies have investigated its expression, functional, and mechanistic involvement in multiple cancer types. Antibody-based therapeutic approaches primarily using antibodies against the tandem repeat domains of MUC16 (e.g., oregovomab and abagovomab) have been the modus operandi for MUC16-targeted therapy, but have met with very limited success. In addition, efforts have been also made to disrupt the functional cooperation of MUC16 and its interacting partners; for example, use of a novel immunoadhesin HN125 to interfere MUC16 binding to mesothelin. Since the identification of CA125 to be MUC16, it is hypothesized to undergo proteolytic cleavage, a process that is considered to be critical in determining the kinetics of MUC16 shedding as well as generation of a cell-associated carboxyl-terminal fragment with potential oncogenic functions. In addition to our experimental demonstration of MUC16 cleavage, recent studies have demonstrated the functional importance of carboxyl terminal fragments of MUC16 in multiple tumor types. Here, we provide how our understanding of the basic biologic processes involving MUC16 influences our approach toward MUC16-targeted therapy. Cancer Res; 75(22); 1–6. ©2015 AACR.

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