Immunotherapy represents a paradigm shift in oncology treatment. The goal of immunotherapy is to overcome immunosuppression induced by a tumour and its microenvironment, thereby allowing the immune ...system to target and kill cancer cells. The immunotherapy era began when the first immune checkpoint inhibitor, ipilimumab, was approved for use almost a decade ago. This therapeutic approach is associated with distinct types of response, including processes such as pseudoprogression (ie, increased tumour burden via radiology, which is not accompanied by clinical deterioration) and hyperprogression (ie, rapid progression of the disease as a result of immunotherapy). In this Review, we focus on therapeutic approaches for patients who progress on immunotherapy. We review the different types of clinical responses associated with immunotherapy and describe treatment options for this population.
Pancreas cancer cells have a tendency to invade along nerves. Such cancerous nerve invasion (CNI) is associated with poor outcome; however, the exact mechanism that drives cancer cells to disseminate ...along nerves is unknown. Immunohistochemical analysis of human pancreatic ductal adenocarcinoma (PDAC) specimens showed overexpression of the L1 cell adhesion molecule (L1CAM) in cancer cells and in adjacent Schwann cells (SC) in invaded nerves. By modeling the neural microenvironment, we found that L1CAM secreted from SCs acts as a strong chemoattractant to cancer cells, through activation of MAP kinase signaling. L1CAM also upregulated expression of metalloproteinase-2 (MMP-2) and MMP-9 by PDAC cells, through STAT3 activation. Using a transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we show that treatment with anti-L1CAM Ab significantly reduces CNI in vivo. We provide evidence of a paracrine response between SCs and cancer cells in the neural niche, which promotes cancer invasion via L1CAM secretion.
The local extension of cancer cells along nerves is a frequent clinical finding for various tumours. Traditionally, nerve invasion was assumed to occur via the path of least resistance; however, ...recent animal models and human studies have revealed that cancer cells have an innate ability to actively migrate along axons in a mechanism called neural tracking. The tendency of cancer cells to track along nerves is supported by various cell types in the perineural niche that secrete multiple growth factors and chemokines. We propose that the perineural niche should be considered part of the tumour microenvironment, describe the molecular cues that facilitate neural tracking and suggest methods for its inhibition.
Summary Oral cancer is the sixth most common cancer worldwide, with a high prevalence in South Asia. Tobacco and alcohol consumption remain the most dominant etiologic factors, however HPV has been ...recently implicated in oral cancer. Surgery is the most well established mode of initial definitive treatment for a majority of oral cancers. The factors that affect choice of treatment are related to the tumor and the patient. Primary site, location, size, proximity to bone, and depth of infiltration are factors which influence a particular surgical approach. Tumors that approach or involve the mandible require specific understanding of the mechanism of bone involvement. This facilitates the employment of mandible sparing approaches such as marginal mandibulectomy and mandibulotomy. Reconstruction of major surgical defects in the oral cavity requires use of a free flap. The radial forearm free flap provides excellent soft tissue and lining for soft tissue defects in the oral cavity. The fibula free flap remains the choice for mandibular reconstruction. Over the course of the past thirty years there has been improvement in the overall survival of patients with oral carcinoma largely due to the improved understanding of the biology of local progression, early identification and treatment of metastatic lymph nodes in the neck, and employment of adjuvant post-operative radiotherapy or chemoradiotherapy. The role of surgery in primary squamous cell carcinomas in other sites in the head and neck has evolved with integration of multidisciplinary treatment approaches employing chemotherapy and radiotherapy either sequentially or concurrently. Thus, larynx preservation with concurrent chemoradiotherapy has become the standard of care for locally advanced carcinomas of the larynx or pharynx requiring total laryngectomy. On the other hand, for early staged tumors of the larynx and pharynx, transoral laser microsurgery has become an effective means of local control of these lesions. Advances in skull base surgery have significantly improved the survivorship of patients with malignant tumors of the paranasal sinuses approaching or involving the skull base. Surgery thus remains the mainstay of management of a majority of neoplasms arising in the head and neck area. Similarly, the role of the surgeon is essential throughout the life history of a patient with a malignant neoplasm in the head and neck area, from initial diagnosis through definitive treatment, post-treatment surveillance, management of complications, rehabilitation of the sequelae of treatment, and finally for palliation of symptoms.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. It thrives in a nutrient-poor environment; however, the mechanisms by which PDAC cells undergo metabolic reprogramming ...to adapt to metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue. Mechanistically, miR-135 accumulates specifically in response to glutamine deprivation and requires ROS-dependent activation of mutant p53, which directly promotes miR-135 expression. Functionally, we found miR-135 targets phosphofructokinase-1 (PFK1) and inhibits aerobic glycolysis, thereby promoting the utilization of glucose to support the tricarboxylic acid (TCA) cycle. Consistently, miR-135 silencing sensitizes PDAC cells to glutamine deprivation and represses tumor growth in vivo. Together, these results identify a mechanism used by PDAC cells to survive the nutrient-poor tumor microenvironment, and also provide insight regarding the role of mutant p53 and miRNA in pancreatic cancer cell adaptation to metabolic stresses.
Although the pathogenic operations of cancer-nerve crosstalk (e.g., neuritogenesis, neoneurogensis, and perineural invasion-PNI) in the peripheral nervous system (PNS) during tumorigenesis, as well ...as the progression of all cancer types is continuing to emerge as an area of unique scientific interest and study, extensive, wide-ranging, and multidisciplinary investigations still remain fragmented and unsystematic. This is especially so in regard to the roles played by extracellular vesicles (EVs), which are lipid bilayer-enclosed nano- to microsized particles that carry multiple-function molecular cargos, facilitate intercellular communication in diverse processes. Accordingly, the biological significance of EVs has been greatly elevated in recent years, as there is strong evidence that they could contribute to important and possibly groundbreaking diagnostic and therapeutic innovations. This can be achieved and the pace of discoveries accelerated through cross-pollination from existing knowledge and studies regarding nervous system physiology and pathology, as well as thoroughgoing collaborations between oncologists, neurobiologists, pathologists, clinicians, and researchers. This article offers an overview of current and recent past investigations on the roles of EVs in cancer-nerve crosstalk, as well as in neural development, physiology, inflammation, injury, and regeneration in the PNS. By highlighting the mechanisms involved in physiological and noncancerous pathological cellular crosstalk, we provide hints that may inspire additional translational studies on cancer-nerve interplay.
Immunohistochemistry (IHC) is the most widely used assay for identification of molecular biomarkers. However, IHC is time consuming and costly, depends on tissue-handling protocols, and relies on ...pathologists' subjective interpretation. Image analysis by machine learning is gaining ground for various applications in pathology but has not been proposed to replace chemical-based assays for molecular detection.
To assess the prediction feasibility of molecular expression of biomarkers in cancer tissues, relying only on tissue architecture as seen in digitized hematoxylin-eosin (H&E)-stained specimens.
This single-institution retrospective diagnostic study assessed the breast cancer tissue microarrays library of patients from Vancouver General Hospital, British Columbia, Canada. The study and analysis were conducted from July 1, 2015, through July 1, 2018. A machine learning method, termed morphological-based molecular profiling (MBMP), was developed. Logistic regression was used to explore correlations between histomorphology and biomarker expression, and a deep convolutional neural network was used to predict the biomarker expression in examined tissues.
Positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristics curve measures of MBMP for assessment of molecular biomarkers.
The database consisted of 20 600 digitized, publicly available H&E-stained sections of 5356 patients with breast cancer from 2 cohorts. The median age at diagnosis was 61 years for cohort 1 (412 patients) and 62 years for cohort 2 (4944 patients), and the median follow-up was 12.0 years and 12.4 years, respectively. Tissue histomorphology was significantly correlated with the molecular expression of all 19 biomarkers assayed, including estrogen receptor (ER), progesterone receptor (PR), and ERBB2 (formerly HER2). Expression of ER was predicted for 105 of 207 validation patients in cohort 1 (50.7%) and 1059 of 2046 validation patients in cohort 2 (51.8%), with PPVs of 97% and 98%, respectively, NPVs of 68% and 76%, respectively, and accuracy of 91% and 92%, respectively, which were noninferior to traditional IHC (PPV, 91%-98%; NPV, 51%-78%; and accuracy, 81%-90%). Diagnostic accuracy improved given more data. Morphological analysis of patients with ER-negative/PR-positive status by IHC revealed resemblance to patients with ER-positive status (Bhattacharyya distance, 0.03) and not those with ER-negative/PR-negative status (Bhattacharyya distance, 0.25). This suggests a false-negative IHC finding and warrants antihormonal therapy for these patients.
For at least half of the patients in this study, MBMP appeared to predict biomarker expression with noninferiority to IHC. Results suggest that prediction accuracy is likely to improve as data used for training expand. Morphological-based molecular profiling could be used as a general approach for mass-scale molecular profiling based on digitized H&E-stained images, allowing quick, accurate, and inexpensive methods for simultaneous profiling of multiple biomarkers in cancer tissues.
The tumor microenvironment (TME) includes a network of cancerous and non-cancerous cells, together with associated blood vessels, the extracellular matrix, and signaling molecules. The TME ...contributes to cancer progression during various phases of tumorigenesis, and interactions that take place within the TME have become targets of focus in cancer therapy development. Extracellular vesicles (EVs) are known to be conveyors of genetic material, proteins, and lipids within the TME. One of the hallmarks of cancer is its ability to reprogram metabolism to sustain cell growth and proliferation in a stringent environment. In this review, we provide an overview of TME EV involvement in the metabolic reprogramming of cancer and stromal cells, which favors cancer progression by enhancing angiogenesis, proliferation, metastasis, treatment resistance, and immunoevasion. Targeting the communication mechanisms and systems utilized by TME-EVs is opening a new frontier in cancer therapy.
Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI, but the contributing ...conditions within the tumor microenvironment are not well understood. Here, we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B-mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2-CCR2 signaling or cathepsin B function significantly impaired PNI
Correlative studies in human specimens demonstrated that cathepsin B-producing macrophages were enriched in invaded nerves, which was associated with increased local tumor recurrence. These findings deepen our understanding of PNI pathogenesis and illuminate how PNI is driven in part by corruption of a nerve repair program. Further, they support the exploration of inhibiting IM recruitment and function as a targeted therapy for PNI.
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