Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped into several protein families that are referred to as tumor necrosis factors, interleukins, interferons, and colony-stimulating factors. In recent years, it has become clear that some of these proteins as well as their receptors are produced in the organisms under physiological and pathological conditions. The exact initiation process of breast cancer is unknown, although several hypotheses have emerged. Inflammation has been proposed as an important player in tumor initiation, promotion, angiogenesis, and metastasis, all phenomena in which cytokines are prominent players. The data here suggest that cytokines play an important role in the regulation of both induction and protection in breast cancer. This knowledge could be fundamental for the proposal of new therapeutic approaches to particularly breast cancer and other cancer-related disorders.

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The role of cytokines in breast cancer development and progression

Breast cancer is the most prevalent cancer among women worldwide and the fifth cause of death among all cancer patients. Breast cancer development is driven by genetic and epigenetic alterations, with the tumor microenvironment (TME) playing an essential role in disease progression and evolution through mechanisms like inflammation promotion. TNF-α is one of the essential pro-inflammatory cytokines found in the TME of breast cancer patients, being secreted both by stromal cells, mainly by tumor-associated macrophages, and by the cancer cells themselves. In this review, we explore the biological and clinical impact of TNF-α in all stages of breast cancer development. First of all, we explore the correlation between TNF-α expression levels at the tumor site or in plasma/serum of breast cancer patients and their respective clinical status and outcome. Secondly, we emphasize the role of TNF-α signaling in both estrogen-positive and -negative breast cancer cells. Thirdly, we underline TNF-α involvement in epithelial-to-mesenchymal transition (EMT) and metastasis of breast cancer cells, and we point out the contribution of TNF-α to the development of acquired drug resistance. Collectively, these data reveal a pro-tumorigenic role of TNF-α during breast cancer progression and metastasis. We systemize the knowledge regarding TNF-α-related therapies in breast cancer, and we explain how TNF-α may act as both a target and a drug in different breast cancer therapeutic approaches. By corroborating the known molecular effects of TNF-α signaling in breast cancer cells with the results from several preclinical and clinical trials, including TNF-α-related clinical observations, we conclude that the potential of TNF-α in breast cancer therapy promises to be of great interest.

The dual role of tumor necrosis factor-alpha (TNF-α) in breast cancer: molecular insights and therapeutic approaches

Long-term prognosis for localized pancreatic cancer remains poor. We sought to assess the benefit of neoadjuvant/preoperative chemotherapy with or without radiotherapy. Prospective studies where gemcitabine with or without radiotherapy was provided before surgery in patients with initially resectable or unresectable disease were reviewed by meta-analysis. Primary outcome was survival, and secondary outcomes were tumor response after therapy, toxicity, surgical exploration, and resection rates. Twenty independent studies with 707 participants were included, 366 with resectable lesions and 341 with unresectable lesions. Seven studies were phase I/II trials, 10 phase II, and 3 prospective cohort studies. Estimated 1- and 2-year survival probabilities after resection were 91.7% (95% confidence interval [CI] 75–100) and 67.2% (95% CI 38–87) for initially resectable patients, and 86.3% (95% CI 78–100) and 54.2% (95% CI 25–100) for initially unresectable patients. The complete/partial response rate was 12% (95% CI 4–23) and 27% (95% CI 18–38) in resectable and unresectable lesions, respectively. The rate of treatment-related grade 3–4 toxicity was 31% (95% CI 21–42). Of resectable patients evaluable after restaging, 91% (95% CI 83–97) underwent surgery, and 82% (95% CI 65–95) of explored patients underwent resection. R0 resections amounted to 89% (95% CI 83–94). Of unresectable patients evaluable after restaging, 39% (95% CI 28–50) underwent surgery, and 68% (95% CI 53–82) of explored patients were resected, with 60% (95% CI 50–71) R0 resections. Current analysis provides marginal support to the assumed benefits of neoadjuvant therapies for patients with resectable cancer, and indicates a potential advantage only for a minority of those with unresectable lesions.

Neoadjuvant/Preoperative Gemcitabine for Patients with Localized Pancreatic Cancer: A Meta-analysis of Prospective Studies

Human leukocyte antigen G (HLA-G) is a non-classical major histocompatibility complex (MHC) class I molecule that, through interaction with its receptors, exerts important tolerogenic functions. Its main physiological expression occurs in placenta where it seems to participate in the maternal tolerance toward the fetus. HLA-G has been studied as a marker of pregnancy complications such as abortion or pre-eclapmsia. Although HLA-G is not expressed in most adult tissues, its ectopic expression has been observed in some diseases such as viral infections, autoimmune disorders, and especially cancer. HLA-G neo-expression in cancer is associated with the capability of tumor cells to evade the immune control. In this review, we will summarize HLA-G biology and how it participates in these physiopathological processes. Special attention will be paid to its role as a diagnostic tool and also as a therapeutic target.

The immunosuppressive molecule HLA-G and its clinical implications.

Pancreatic cancer accounts for approximately 3% of cancer deaths in Europe. Locally advanced pancreatic cancer (LAPC) involves vascular structures, and resectability is low, with a median survival time of 6 to 11 months. We conducted a prospective, nonrandomized study of patients with LAPC to assess the effect of stereotactic body radiotherapy (SBRT) on local response, pain control, and quality of life (QOL). Twenty-three patients with histologically confirmed LAPC underwent SBRT. Radiotherapy (30 Gy) was delivered in three fractions, and treatment toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE v. 3.0). All patients received also gemcitabine chemotherapy and were followed up until death. Local control was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, pain control was assessed with a visual analog scale, and QOL was assessed with the SF-36 instrument (Italian v. 1.6). No grade 2 or higher acute or late toxicity was observed. The overall local response ratio was 82.6% (14 partial response, 2 complete response, 3 stable disease). SBRT showed a good short-term efficacy in controlling both pain and QOL. Median survival was 10.6 months, with a median follow-up of 9 months. The LAPC became resectable in 8% of the patients. Median time to progression of disease was 7.3 months. Six patients developed early metastatic disease. The SBRT method is a promising treatment for LAPC. Local control rates, even compared to historical data from conventional radiotherapy, can be achieved with minimal toxicity. Resectability can also be achieved.

Unresectable Locally Advanced Pancreatic Cancer: A Multimodal Treatment Using Neoadjuvant Chemoradiotherapy (Gemcitabine Plus Stereotactic Radiosurgery) and Subsequent Surgical Exploration

Breast cancer (BC) is a complex, multi-stage disease involving deregulation of different signaling cascades. The present study was conducted to determine the extent of apoptosis, angiogenesis, inflammation, and oxidative stress in patients with different stages of BC as an approach to disease biological behavior. Therefore, plasma levels of soluble (s) Fas, bcl-2 as antiapoptotic indices; interleukin (IL)-8, tumor necrosis factor (TNF)-α as apoptotic, inflammatory, angiogenic indices; lipid peroxides (LPO), nitric oxide (NO) as oxidative stress and angiogenic indices were measured in patients with BC. Thirty-seven newly diagnosed patients with BC, 30 patients with benign breast masses, and 30 healthy controls were recruited. Plasma levels of sFas, bcl-2, IL-8, and TNF-α were measured by immunosorbent assay kits and LPO and NO by chemical methods. Plasma sFas and LPO were significantly higher in BC patients versus benign breast masses and healthy controls (P < 0.0001). Bcl-2, IL-8, TNF-α, and NO were significantly higher in benign breast masses (P < 0.0001, P < 0.037, P < 0.0001, P < 0.001) and BC (P < 0.0001) versus controls and in BC versus benign breast masses (P < 0.0001). sFas, bcl-2, IL-8, TNF-α, LPO, and NO were increased with advanced tumor stages. There were positive correlations between sFas, bcl-2, IL-8 TNF-α, LPO, and NO. BC tumor cells overexpress bcl-2 and sFas to secure their outgrowth and survival. However, this coincides with activation of physiologic regulatory mechanisms, as increased IL-8, TNF-α, LPO, and NO, which try to stop tumor cells by inducing apoptosis. Outcompeting of these mechanisms result in tumor progression as IL-8, TNF-α, and NO are also angiogenic stimulators.

Apoptosis, angiogenesis, inflammation, and oxidative stress: basic interactions in patients with early and metastatic breast cancer

Recent studies indicate an ectopic upregulation of the human leukocyte antigen G (HLA-G) in tumor cells that may favor their escape from antitumor immune responses. The role of HLA-G in breast cancer has not been defined. Other studies showed that HLA-G transcription may be silenced by epigenetic mechanisms or activated by stress. This work aimed to clarify the expression of HLA-G protein, estimate the possible prognostic role of HLA-G expression and identify if this expression is linked to the DNA index (DI) and S phase fraction (SPF) in breast cancer. HLA-G protein expression and the DNA parameters were studied by flow cytometry and serum secreted HLA-G (sHLA-G) levels were detected by enzyme-linked immunosorbent assay (ELISA) in 45 breast cancer patients and 40 female blood donors as healthy donors. Surface HLA-G was expressed on 40% and the cytoplasmic pattern with no membrane association in 24.4% of the malignant specimens. There was an increased serum sHLA-G level in patients as compared with controls. There were negative correlations between cytoplasmic HLA-G and both DI and SPF and between preoperative sHLA-G and SPF with no relations with patients' clinical outcome. We cannot establish that HLA-G protein can be a useful prognostic marker, but sHLA-G may be used as a tumor marker in breast cancer patients.

HLA-G and its relation to proliferation index in detection and monitoring breast cancer patients.

Background: The development of effective treatments against metastatic cancers, including breast cancer, is among the most important challenges in current experimental and clinical cancer research. We recently demonstrated that Walterinnesia aegyptia venom (WEV), either alone or in combination with silica nanoparticles (WEV+NP), resulted in the growth arrest and apoptosis of different cancer cell lines. Aims: In the present study, we evaluated the impact of WEV alone and WEV+NP on human breast cancer cells isolated from cancer biopsies. Methods: The potential effects of WEV alone and WEV+NP on the proliferation, induction of apoptosis and generation of free radicals in breast cancer cells isolated from 80 patients clinically diagnosed with breast cancer were evaluated by flow cytometry and ELISA. Results: WEV alone and WEV+NP inhibited the proliferation, altered the cell cycle and enhanced the induction of apoptosis of the breast cancer cells by increasing the activities of caspase-3, caspase-8 and caspase-9. In addition, the combination of WEV and NP robustly sensitized the breast cancer cells to growth arrest and apoptosis by increasing the generation of free radicals, including reactive oxygen species (ROS), hydroperoxide and nitric oxide. The combination of WEV with NP significantly enhanced the anti-tumor effect of WEV in breast cancer cells. Conclusion: Our data indicate the therapeutic potential of the nanoparticle-sustained delivery of snake venom for the treatment of breast cancer.

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Increased susceptibility to apoptosis and growth arrest of human breast cancer cells treated by a snake venom-loaded silica nanoparticles.

Fetus in fetu is a rare abnormality secondary to the abnormal embryogenesis in a diamniotic, monochorionic pregnancy. It is a rare pathological condition and fewer than 100 cases have been reported in the literature. A 2 month old girl with an abdominal mass since birth, was referred to the Cancer Institute with a suspected diagnosis of a Wilms' tumor. Conventional radiograph of the abdomen revealed a mass containing numerous calcifications. CT scan showed a heterogeneous retroperitoneal mass containing well-defined calcified structures. The decision was made to recommend surgical exploration and the mass was successfully excised. Physical examination of the mass with review of literature confirmed the diagnosis of fetus in fetu. Although it is a rare condition imaging may play an important role in the correct prospective diagnosis of fetus in fetu. Surgical excision is the recommended treatment.

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Fetus in fetu: a case report

Almost 30% of patients with pancreatic cancer have locally advanced tumours in absence of distant metastasis. Surgical resection is often contraindicated. The combination of gemcitabine with concurrent radiation therapy is a promising new approach that is being investigated for treating patients' unresectable pancreatic cancer. This work aims at assessing the efficacy of preoperative gemcitabine based chemo-radiotherapy in increasing the resectability rate for patients' locally advanced pancreatic cancer. From March 2006 to November 2007, 25 patients with locally advanced non metastatic pancreatic cancer were treated by preoperative gemcitabine based chemo-radiotherapy. The radiation dose was 54 Gray in 30 fractions over 6 weeks prescribed to the isocenter. Gemcitabine (300 mg/m2) was given through a 30 minute intravenous infusion. This was done 30 minutes before the radiation sitting on a weekly basis throughout the radiotherapy course. Approximately 6 weeks after the completion of chemo radiation, an evaluation was performed regarding tumour response and resectability as well as acute toxicity. Pancreaticoduodenectomy was performed for operable patients with surgical reconstruction. Patients who achieved complete resection (CR) numbered 2 (8%), while those achieving partial resection (PR) totalled 11 (44%); six of these patients were considered ro be operable. Thus Pancreaticoduodenectomy was performed on 8 patients (2 with CR and 6 with PR) with surgical reconstruction. Patients who had a stable disease numbered 4 (16%), and those with progressive diseases included a group of eight (32%). The postoperative 30 day mortality occurred only in one patient (12.5%). Acute toxicity of chemoradiation occurred in the form of grade I leucopoenia and thrombocytopenia. Hepatic toxicity, nausea, and vomiting were found in 8 patients (32%), 10 patients (40%) and 4 patients (16%), respectively. The postoperative 30 day mortality occurred only in 1 patient. Also, minor biliary leakage and leakage from gastrointestinal anaestomosis both occurred in a single patient. Out of the 8 patients who underwent radical surgical resection, only one developed local recurrence and simultaneous liver metastasis during the follow up period. The median survival of all patients was 12 months. Preoperative gemcitabine based chemoradiation might benefit patients with locally advanced non metastatic pancreatic cancer by increasing the resectability without significant acute toxicity.

https://link.springer.com/content/pdf/10.1186%2F1755-7682-2-7.pdf

Doaa W. Maximous

Papers

Apoptosis, angiogenesis, inflammation, and oxidative stress: basic interactions in patients with early and metastatic breast cancer

HLA-G and its relation to proliferation index in detection and monitoring breast cancer patients.

Increased susceptibility to apoptosis and growth arrest of human breast cancer cells treated by a snake venom-loaded silica nanoparticles.

Fetus in fetu: a case report

Preoperative gemcitabine based chemo-radiotherapy in locally advanced non metastatic pancreatic adenocarcinoma