Cancer Medicine

Natural bicyclic sesquiterpenes, β‐caryophyllene (BCP) and β‐caryophyllene oxide (BCPO), are present in a large number of plants worldwide. Both BCP and BCPO (BCP(O)) possess significant anticancer activities, affecting growth and proliferation of numerous cancer cells. Nevertheless, their antineoplastic effects have hardly been investigated in vivo. In addition, both compounds potentiate the classical drug efficacy by augmenting their concentrations inside the cells. The mechanisms underlying the anticancer activities of these sesquiterpenes are poorly described. BCP is a phytocannabinoid with strong affinity to cannabinoid receptor type 2 (CB₂), but not cannabinoid receptor type 1 (CB₁). In opposite, BCP oxidation derivative, BCPO, does not exhibit CB_1/2 binding, thus the mechanism of its action is not related to endocannabinoid system (ECS) machinery. It is known that BCPO alters several key pathways for cancer development, such as mitogen‐activated protein kinase (MAPK), PI3K/AKT/mTOR/S6K1 and STAT3 pathways. In addition, treatment with this compound reduces the expression of procancer genes/proteins, while increases the levels of those with proapoptotic properties. The selective activation of CB₂ may be considered a novel strategy in pain treatment, devoid of psychoactive side effects associated with CB₁ stimulation. Thus, BCP as selective CB₂ activator may be taken into account as potential natural analgesic drug. Moreover, due to the fact that chronic pain is often an element of cancer disease, the double activity of BCP, anticancer and analgesic, as well as its beneficial influence on the efficacy of classical chemotherapeutics, is particularly valuable in oncology. This review is focused on anticancer and analgesic activities of BCP and BCPO, the mechanisms of their actions, and potential therapeutic utility.

As one of the Ras‐associated proteins, Rap1A has been linked to cancer initiation and development. However, the precise function of Rap1A in ovarian cancer is still not understood. Here, we show that Rap1A promotes ovarian cancer tumorigenesis and metastasis via stimulating cell proliferation, migration and invasion both in vivo and in vitro. Mechanistic study showed that Rap1A activates extracellular signal‐regulated kinase (ERK), p38 mitogen‐activated protein kinase (MAPK) and Notch pathways, leading to the enhanced expression of several epithelial‐mesenchymal transition (EMT) markers such as slug, zeb1, vimentin, fibronectin, and MMP9. However, the pretreatment of Rap1A‐overexpressing cells with the Notch inhibitor DAPT or ERK inhibitor (U0126) inhibited the up‐regulated expression of those molecules. These findings provide the first evidence linking Rap1A with ovarian cancer development through the ERK/p38 and Notch signaling pathways, indicating that Rap1A may be used as a novel diagnostic marker or a therapeutic target for ovarian cancer.

Primary care physicians can serve as both facilitators and barriers to cancer screening, particularly for under‐screened groups such as immigrant patients. The objective of this study was to inform physician‐targeted interventions by identifying primary care physician characteristics associated with cancer screening for their eligible patients, for their eligible immigrant patients, and for foreign‐trained physicians, for their eligible immigrant patients from the same world region. A population‐based retrospective cohort study was performed, looking back 3 years from 31 December 2010. The study was performed in urban primary care practices in Ontario, Canada's largest province. A total of 6303 physicians serving 1,156,627 women eligible for breast cancer screening, 2,730,380 women eligible for cervical screening, and 2,260,569 patients eligible for colorectal screening participated. Appropriate breast screening was defined as at least one mammogram in the previous 2 years, appropriate cervical screening was defined as at least one Pap test in the previous 3 years, and appropriate colorectal screening as at least one fecal occult blood test in the previous 2 years or at least one colonoscopy or barium enema in the previous 10 years. Just fewer than 40% of physicians were female, and 26.1% were foreign trained. In multivariable analyses, physicians who attended medical schools in the Caribbean/Latin America, the Middle East/North Africa, South Asia, and Western Europe were less likely to screen their patients than Canadian graduates. South Asian‐trained physicians were significantly less likely to screen South Asian women for cervical cancer than other foreign‐trained physicians who were seeing region‐congruent patients (adjusted odds ratio: 0.56 [95% confidence interval 0.32–0.98] versus physicians from the USA, Australia and New Zealand). South Asian patients were the most vulnerable to under‐screening, and decreasing patient income quintile was consistently associated with lower likelihood of screening, although less so for immigrant patients. This study highlights certain physician characteristics that are associated with cancer screening for eligible patients, including immigrant patients, and that should be considered when designing physician‐targeted interventions. We have also highlighted an ethnic community, South Asians, which requires particular attention, both among its patients and its primary care providers. Future research should further explore the reasons for these findings.

Angiogenesis has been regarded as essential for tumor growth and progression. Studies of many human tumors, however, suggest that their microcirculation may be provided by nonsprouting vessels and that a variety of tumors can grow and metastasize without angiogenesis. Vessel co‐option, where tumor cells migrate along the preexisting vessels of the host organ, is regarded as an alternative tumor blood supply. Vessel co‐option may occur in many malignancies, but so far mostly reported in highly vascularized tissues such as brain, lung, and liver. In primary and metastatic lung cancer and liver metastasis from different primary origins, as much as 10–30% of the tumors are reported to use this alternative blood supply. In addition, vessel co‐option is introduced as a potential explanation of antiangiogenic drug resistance, although the impact of vessel co‐option in this clinical setting is still to be further explored. In this review we discuss tumor vessel co‐option with specific examples of vessel co‐option in primary and secondary tumors and a consideration of the clinical implications of this alternative tumor blood supply.

Of all the gynecologic tumors, ovarian cancer (OC) is known to be the deadliest. Advanced‐stages of OC are linked with high morbidity and low survival rates despite the immense amount of research in the field. Shortage of promising screening tools for early‐stage detection is one of the major challenges linked with the poor survival rate for patients with OC. In OC, therapeutic management is used with multidisciplinary approaches that includes debulking surgery, chemotherapy, and (rarely) radiotherapy. Recently, there is an increasing interest in using immunomodulation for treating OC. Relapse rates are high in this malignancy and averages around every 2‐years. Further treatments after the relapse are more intense, increasing the toxicity, resistance to chemotherapy drugs, and financial burden to patients with poor quality‐of‐life. A procedure that has been studied to help reduce the morbidity rate involves pre‐sensitizing cancer cells with standard therapy in order to produce optimal results with minimum dosage. Utilizing such an approach, platinum‐based agents are effective due to their increased response to platinum‐based chemotherapy in relapsed cases. These chemo‐drugs also help address the issue of drug resistance. After conducting an extensive search with available literature and the resources for clinical trials, information is precisely documented on current research, biomarkers, options for treatment and clinical trials. Several schemes for enhancing the therapeutic responses for OC are discussed systematically in this review with an attempt in summarizing the recent developments in this exciting field of translational/clinical research.

Cell‐free plasma DNA (cfDNA) and mimicking circulating tumor cells (mCTCs) have demonstrated tremendous potential for molecular diagnosis of cancer and have been rapidly implemented in specific settings. However, widespread clinical adoption still faces some obstacles. The purpose was to compare the performance of a BEAMing (beads, emulsion, amplification, and magnetics) assay (OncoBEAM™‐epidermal growth factor receptor [EGFR] [Sysmex Inostics]) and a next‐generation sequencing assay (NGS; 56G Oncology panel kit, Swift Bioscience) to detect the p.T790M EGFR mutation in cfDNA of non‐small cell lung cancer (NSCLC) patients. CfDNA samples (n = 183) were collected within our hospital from patients having a known EGFR sensitizing mutation, and presenting disease progression while under first‐line therapy. EGFR mutations were detected using NGS in 42.1% of samples during progression in cfDNA. Testing using the OncoBEAM™‐EGFR assay enabled detection of the p.T790M EGFR mutation in 40/183 NSCLC patients (21.8%) versus 20/183 (10.9%), using the NGS assay. Samples that were only positive with the OncoBEAM™‐EGFR assay had lower mutant allelic fractions (Mean = 0.1304%; SD ± 0.1463%). In addition, we investigated the detection of p.T790M in mCTCs using H1975 cells. These cells spiked into whole blood were enriched using the ClearCellFX1 microfluidic device. Using the OncoBEAM™‐EGFR assay, p.T790M was detected in as few as 1.33 tumoral cells/mL. Overall, these findings highlight the value of using the OncoBEAM™‐EGFR to optimize detection of the p.T790M mutation, as well as the complementary clinical value that each of the mutation detection assay offers: NGS enabled the detection of mutations in other oncogenes that may be relevant to secondary resistance mechanisms, whereas the OncoBEAM™‐EGFR assay achieved higher sensitivity for detection of clinically actionable mutations.