Biophysical phenotype mixtures reveal advantages for tumor muscle invasion in vivo.

Bladder, colon, gastric, prostate, and uterine cancers originate in organs surrounded by laminin-coated smooth muscle. In human prostate cancer, tumors that are organ confined, without extracapsular extension through muscle, have an overall cancer survival rate of up to 97% compared with 32% for metastatic disease. Our previous work modeling extracapsular extension reported the blocking of tumor invasion by mutation of a laminin-binding integrin called α6β1.

Cohesive cancer invasion of the biophysical barrier of smooth muscle.

Smooth muscle is found around organs in the digestive, respiratory, and reproductive tracts. Cancers arising in the bladder, prostate, stomach, colon, and other sites progress from low-risk disease to high-risk, lethal metastatic disease characterized by tumor invasion into, within, and through the biophysical barrier of smooth muscle. We consider here the unique biophysical properties of smooth muscle and how cohesive clusters of tumor use mechanosensing cell-cell and cell-ECM (extracellular matrix) adhesion receptors to move through a structured muscle and withstand the biophysical forces to reach distant sites.

The Tumor Microenvironments of Lethal Prostate Cancer.

Localized prostate cancer (confined to the gland) generally is considered curable, with nearly a 100% 5-year-survival rate. When the tumor escapes the prostate capsule, leading to metastasis, there is a poorer prognosis and higher mortality rate, with 5-year survival dropping to less than 30%. A major research question has been to understand the transition from indolent (low risk) disease to aggressive (high risk) disease.

A Method to Reuse Archived H&E Stained Histology Slides for a Multiplex Protein Biomarker Analysis.

Archived Hematoxylin and Eosin (H&E) stained pathology slides are routinely stored to index formalin-fixed paraffin-embedded (FFPE) sample tissue blocks. FFPE blocks are clinically annotated human tumor specimens that can be valuable in studies decades after the tissue is collected. If stored properly, they have the potential to yield a valuable number of serial sectioned slides for diagnostic or research purposes.

Kallikrein 6 protease advances colon tumorigenesis induction of the high mobility group A2 protein.

Kallikrein-related peptidase 6 (KLK6) overexpression is commonly observed in primary tumors of colorectal cancer (CRC) patients and has been associated with tumor aggressiveness, metastasis, and poor prognosis. We previously established a unique contribution of KLK6 in colon cancer metastasis via a specific network of microRNAs and mRNAs. Here we evaluated the cellular functions of KLK6 protease in Caco-2 colon adenocarcinoma cell line after introduction of the enzymatically active or inactive form of the enzyme.

Centrosome loss results in an unstable genome and malignant prostate tumors.

Localized, nonindolent prostate cancer (PCa) is characterized by large-scale genomic rearrangements, aneuploidy, chromothripsis, and other forms of chromosomal instability (CIN), yet how this occurs remains unclear. A well-established mechanism of CIN is the overproduction of centrosomes, which promotes tumorigenesis in various mouse models. Therefore, we developed a single-cell assay for quantifying centrosomes in human prostate tissue.

Gene Editing of α6 Integrin Inhibits Muscle Invasive Networks and Increases Cell-Cell Biophysical Properties in Prostate Cancer.

Human prostate cancer confined to the gland is indolent (low-risk), but tumors outside the capsule are aggressive (high-risk). Extracapsular extension requires invasion within and through a smooth muscle-structured environment. Because integrins respond to biomechanical cues, we used a gene editing approach to determine if a specific region of laminin-binding α6β1 integrin was required for smooth muscle invasion both and .

Integrin α6β4E variant is associated with actin and CD9 structures and modifies the biophysical properties of cell-cell and cell-extracellular matrix interactions.

Integrin α6β4 is an essential, dynamic adhesion receptor for laminin 332 found on epithelial cells, required for formation of strong cell-extracellular matrix (ECM) adhesion and induced migration, and coordinated by regions of the β4C cytoplasmic domain. β4E, a unique splice variant of β4 expressed in normal tissue, contains a cytoplasmic domain of 231 amino acids with a unique sequence of 114 amino acids instead of β4C's canonical 1089 amino acids. We determined the distribution of α6β4E within normal human glandular epithelium and its regulation and effect on cellular biophysical properties.

A method of quantifying centrosomes at the single-cell level in human normal and cancer tissue.

Centrosome abnormalities are emerging hallmarks of cancer. The overproduction of centrosomes (known as centrosome amplification) has been reported in a variety of cancers and is currently being explored as a promising target for therapy. However, to understand different types of centrosome abnormalities and their impact on centrosome function during tumor progression, as well as to identify tumor subtypes that would respond to the targeting of a centrosome abnormality, a reliable method for accurately quantifying centrosomes in human tissue samples is needed.

A new species of Harris from southern Arizona (Erebidae, Arctiinae).

is described from southeastern Arizona. Although superficially similar to species of Grote, structural and molecular variation shows it to be most closely related to (Cassino). Adults, genitalic structure, eggs, and first instar larvae are described and illustrated.

Novel Regulation of Integrin Trafficking by Rab11-FIP5 in Aggressive Prostate Cancer.

The laminin-binding integrins, α3β1 and α6β1, are needed for tumor metastasis and their surface expression is regulated by endocytic recycling. β1 integrins share the Rab11 recycling machinery, but the trafficking of α3β1 and α6β1 are distinct by an unknown mechanism. Using a mouse PDX tumor model containing human metastatic prostate cancer, Rab11 family interacting protein 5 (Rab11-FIP5) was identified as a lead candidate for α6β1 trafficking.

Does Mutated Oncogene Attenuate the Effect of Sulindac in Colon Cancer Chemoprevention?

The NSAID sulindac has been successfully used alone or in combination with other agents to suppress colon tumorigenesis in patients with genetic predisposition and also showed its efficacy in prevention of sporadic colon adenomas. At the same time, some experimental and clinical reports suggest that a mutant oncogene may negate sulindac antitumor efficacy. To directly assess sulindac activity at suppressing premalignant lesions carrying K-RAS mutation, we utilized a novel mouse model with an inducible colon-specific expression of the mutant oncogene ( ).

Bioactivity and prostate tissue distribution of metformin in a preprostatectomy prostate cancer cohort.

Metformin has recently been shown to have potential to reduce prostate cancer risk. We conducted a randomized, double-blind, placebo-controlled trial to determine the modulating effects of metformin on tissue and systemic biomarkers of drug activity and its distribution into the prostate tissue. Twenty patients with prostate cancer scheduled to undergo prostatectomy were randomly assigned to receive either extended-release metformin or placebo for a median of 34 days before surgery.

The Cohesive Metastasis Phenotype in Human Prostate Cancer.

A critical barrier for the successful prevention and treatment of recurrent prostate cancer is detection and eradication of metastatic and therapy-resistant disease. Despite the fall in diagnoses and mortality, the reported incidence of metastatic disease has increased 72% since 2004. Prostate cancer arises in cohesive groups as intraepithelial neoplasia, migrates through muscle and leaves the gland via perineural invasion for hematogenous dissemination.

A basal cell defect promotes budding of prostatic intraepithelial neoplasia.

Basal cells in a simple secretory epithelium adhere to the extracellular matrix (ECM), providing contextual cues for ordered repopulation of the luminal cell layer. Early high-grade prostatic intraepithelial neoplasia (HG-PIN) tissue has enlarged nuclei and nucleoli, luminal layer expansion and genomic instability. Additional HG-PIN markers include loss of α6β4 integrin or its ligand laminin-332, and budding of tumor clusters into laminin-511-rich stroma.

Characterization of Laminin Binding Integrin Internalization in Prostate Cancer Cells.

Laminin binding integrins α6 (CD49f) and α3 (CD49c) are persistently but differentially expressed in prostate cancer (PCa). Integrin internalization is an important determinant of their cell surface expression and function. Using flow cytometry, and first order kinetic modeling, we quantitated the intrinsic internalization rates of integrin subunits in a single cycle of internalization.

Laminin-binding integrin gene copy number alterations in distinct epithelial-type cancers.

Background: The laminin-binding integrin (LBI) family are cell adhesion molecules that are essential for invasion and metastasis of human epithelial cancers and cell adhesion mediated drug resistance. We investigated whether copy number alteration (CNA) or mutations of a five-gene signature (ITGB4, ITGA3, LAMB3, PLEC, and SYNE3), representing essential genes for LBI adhesion, would correlate with patient outcomes within human epithelial-type tumor data sets currently available in an open access format.

Methods: We investigated the relative alteration frequency of an LBI signature panel (integrin β4 (ITGB4), integrin α3 (ITGA3), laminin β3 chain (LAMB3), plectin (PLEC), and nesprin 3 (SYNE3)), independent of the epithelial cancer type, within publically available and published data using cBioPortal and Oncomine software.

Time-serial Assessment of Drug Combination Interventions in a Mouse Model of Colorectal Carcinogenesis Using Optical Coherence Tomography.

Optical coherence tomography (OCT) is a high-resolution, nondestructive imaging modality that enables time-serial assessment of adenoma development in the mouse model of colorectal cancer. In this study, OCT was utilized to evaluate the effectiveness of interventions with the experimental antitumor agent α-difluoromethylornithine (DFMO) and a nonsteroidal anti-inflammatory drug sulindac during early [chemoprevention (CP)] and late stages [chemotherapy (CT)] of colon tumorigenesis. Biological endpoints for drug interventions included OCT-generated tumor number and tumor burden.

Schwann Cells Increase Prostate and Pancreatic Tumor Cell Invasion Using Laminin Binding A6 Integrin.

Human pancreatic and prostate cancers metastasize along nerve axons during perineural invasion. The extracellular matrix laminin class of proteins is an abundant component of both myelinated and non-myelinated nerves. Analysis of human pancreatic and prostate tissue revealed both perineural and endoneural invasion with Schwann cells surrounded or disrupted by tumor, respectively.

Combined micro CT and histopathology for evaluation of skeletal metastasis in live animals.

Bone is a favored site for solid tumor metastasis, especially among patients with breast, lung or prostate carcinomas. Micro CT is a powerful and inexpensive tool that can be used to investigate tumor progression in xenograft models of human disease. Many previous studies have relied on terminal analysis of harvested bones to document metastatic tumor activity.

Nanoparticle delivery of an AKT/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer.

The K-ras mutation in pancreatic cancer can inhibit drug delivery and increase drug resistance. This is exemplified by the therapeutic effect of PH-427, a small molecule inhibitor of AKT/PDK1, which has shown a good therapeutic effect against a BxPC3 pancreatic cancer model that has K-ras, but has a poor therapeutic effect against a MiaPaCa-2 pancreatic cancer model with mutant K-ras. To increase the therapeutic effect of PH-427 against the MiaPaCa-2 pancreatic cancer model with mutant K-ras, we encapsulated PH-427 into poly(lactic-co-glycolic acid) nanoparticles (PNP) to form drug-loaded PH-427-PNP.

Intracellular modifiers of integrin alpha 6p production in aggressive prostate and breast cancer cell lines.

Cancer metastasis is a multi-step process in which tumor cells gain the ability to invade beyond the primary tumor and colonize distant sites. The mechanisms regulating the metastatic process confer changes to cell adhesion receptors including the integrin family of receptors. Our group previously discovered that the α6 integrin (ITGA6/CD49f) is post translationally modified by urokinase plasminogen activator (uPA) and its receptor, urokinase plasminogen activator receptor (uPAR), to form the variant ITGA6p.

Determination of Optimum Formalin Fixation Duration for Prostate Needle Biopsies for Immunohistochemistry and Quantum Dot FISH Analysis.

Prostate biopsy is the key clinical specimen for disease diagnosis. However, various conditions used during biopsy processing for histologic analysis may affect the performance of diagnostic tests, such as hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), or in situ hybridization (ISH). One such condition that may affect diagnostic test performance is fixation duration in 10% neutral buffered formalin (NBF).

Increased aPKC Expression Correlates with Prostatic Adenocarcinoma Gleason Score and Tumor Stage in the Japanese Population.

Background. Levels of the protein kinase aPKC have been previously correlated with prostate cancer prognosis in a British cohort. However, prostate cancer incidence and progression rates, as well as genetic changes in this disease, show strong ethnic variance, particularly in Asian populations.