The mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK) signaling pathway serves an integral role in growth, proliferation, differentiation, migration, and survival of all mammalian cells. Aberrant signaling of this pathway is often observed in several types of hematologic and solid malignancies. The most frequent insult to this signaling cascade, leading to its constitutive activation, is to the serine/threonine kinase rapidly accelerating fibrosarcoma (RAF). Considering this, the development and approval of various small-molecule inhibitors targeting the MAPK/ERK pathway has become a mainstay of treatment as either mono- or combination therapy in these cancers. Although effective initially, a major clinical barrier with these inhibitors is the relapse of patients due to drug resistance. Knowledge of the mechanisms of resistance to these drugs is still premature, highlighting the need for a more in-depth understanding of how patients become insensitive to these pharmacologic interventions. Herein, we will succinctly summarize the milestones in the approval of select MAPK/ERK pathway inhibitors, their use in patients, and major modes of resistance.

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BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers.

Breast cancer is the most common malignant tumors in females. Although the conventional treatment has demonstrated a certain effect, some limitations still exist. The Rho guanosine triphosphatase (GTPase) Cdc42 (Cell division control protein 42 homolog) is often upregulated by some cell surface receptors and oncogenes in breast cancer. Cdc42 switches from inactive guanosine diphosphate (GDP)-bound to active GTP-bound though guanine-nucleotide-exchange factors (GEFs), results in activation of signaling cascades that regulate various cellular processes such as cytoskeletal changes, proliferation and polarity establishment. Targeting Cdc42 also provides a strategy for precise breast cancer therapy. In addition, Cdc42 is a potential target for several types of non-coding RNAs including microRNAs and lncRNAs. These non-coding RNAs is extensively involved in Cdc42-induced tumor processes, while many of them are aberrantly expressed. Here, we focus on the role of Cdc42 in cell morphogenesis, proliferation, motility, angiogenesis and survival, introduce the Cdc42-targeted non-coding RNAs, as well as present current development of effective Cdc42-targeted inhibitors in breast cancer.

Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding RNAs.

Purpose: The role of Rac1 in cancer survival has been widely studied. However, the prognostic and clinicopathological value of Rac1 remains inconclusive. We performed a meta-analysis to clarify the role of Rac1 in cancer survival as well as its association with clinicopathological features. Methods: Eligible studies were searched from PubMed, Cochrane Library, Embase, and Web of Science databases. The pooled hazard ratios (HRs) and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to detect the prognostic and clinicopathological role of Rac1. Results: A total of 14 studies including 1793 patients were enrolled in the present meta-analysis. Pooled HR for overall survival (OS) (HR=2.02, 95% CI: 1.70-2.39) and disease-free survival (DFS) (HR=2.64, 95% CI: 1.71-4.09) indicated a significant poor prognostic effect for Rac1. Positive Rac1 expression was found to be correlated with tumor stage, blood vessel invasion, and lymph metastasis, but not with histological differentiation. Sensitivity test showed no single study altered OS or DFS significantly. No publication bias was detected by Egger's test and Begg's funnel plot test. Conclusion: This meta-analysis indicated that Rac1 could be used as a potential marker to predict cancer prognosis. Additionally, Rac1 expression was associated with the malignancy-related phenotype.

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Prognostic and Clinicopathological Value of Rac1 in Cancer Survival: Evidence from a Meta-Analysis.

Cell polarity, the asymmetric distribution of proteins, organelles, and cytoskeleton, plays an important role in development, homeostasis, and disease. Understanding the mechanisms that govern cell polarity is critical for creating strategies to treat developmental defects, accelerate tissue regeneration, and hinder cancer progression. This review focuses on the role of cell polarity in a number of physiological processes, including asymmetric division, cell migration, immune response mediated by T lymphocytes, and cancer progression and metastasis, and highlights microfabrication techniques to systematically parse the role of microenvironmental cues in the regulation of cell polarity.

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Polarity as a physiological modulator of cell function.

Endometrial stromal sarcoma (ESS) is a rare uterine malignancy that features different prognoses for its high- and low-grade subtypes. We investigated the diagnostic accuracy of magnetic resonance (MR) imaging in diagnosing and differentiating between high- and low-grade ESS. We retrospectively reviewed the preoperative pelvic MR images of consecutive patients who received histologically confirmed diagnoses of high-grade ESS (n = 11) and low-grade ESS (n = 9) and T2-hyperintense leiomyoma (n = 16). Two radiologists independently evaluated imaging features in T1-, T2-, and diffusion-weighted and contrast-enhanced MR images. Statistical analysis included Mann-Whitney tests and Fisher’s exact test, with sensitivity, specificity and diagnostic accuracy of imaging features. High-grade ESS was associated with significantly more extensive necrosis and hemorrhage and distinct feather-like enhancement compared with low-grade ESS (P < .05 for all). The feather-like enhancement pattern yielded a diagnostic accuracy of 95%, sensitivity of 91%, and specificity of 100% in differentiating high-grade from low-grade ESS. This imaging characteristic was significantly superior to the necrosis (80%, P = .033) or hemorrhage (75%, P = .007). Both high- and low-grade ESS demonstrated T2 hypointense bands, marginal nodules, intratumoral nodules, and worm-like intra-myometrial nodules, and their tumor apparent diffusion coefficient (ADC) values were significantly lower than those of T2-hyperintense leiomyomas (P < .001). Diffusion-weighted MR imaging is useful in diagnosing ESS against T2-hyperintense leiomyomas, and contrast enhancement aids in further differentiating between high- and low-grade ESS.

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Utility of diffusion-weighted and contrast-enhanced magnetic resonance imaging in diagnosing and differentiating between high- and low-grade uterine endometrial stromal sarcoma.

The change of cell polarity is usually associated with invasion and metastasis. Partial reverse cell polarity in IDC-NOS may play a role in lymphatic tumor spread. Rac1 is a kind of polarity related protein. It plays an important role in invasion and metastasis in tumors. We here investigated the expression of Rac1 and partial reverse cell polarity status in breast cancer and evaluated their value for prognosis in breast cancer. The association of the expression of Rac1 and MUC-1 with clinicopathological parameters and prognostic significance was evaluated in 162 cases of IDC-NOS paraffin-embedded tissues by immunohistochemical method. The Rac1 messenger RNA expression was measured by real-time polymerase chain reaction in 30 breast cancer patients, which was divided into two groups of partial reverse cell polarity and no partial reverse cell polarity. We found that lymph node metastasis of partial reverse cell polarity patients was higher than no partial reverse cell polarity patients (Z = -4.030, p = 0.000). Rac1 was upregulated in partial reverse cell polarity group than no partial reverse cell polarity group (Z = -3.164, p = 0.002), and there was correlationship between the expression of Rac1 and partial reverse cell polarity status (rs = 0.249, p = 0.001). The level of Rac1 messenger RNA expression in partial reverse cell polarity group was significantly higher compared to no partial reverse cell polarity group (t = -2.527, p = 0.017). Overexpression of Rac1 and partial reverse cell polarity correlates with poor prognosis of IDC-NOS patients (p = 0.011). Partial reverse cell polarity and lymph node metastasis remained as independent predictors for poor disease-free survival of IDC-NOS (p = 0.023, p = 0.046). Our study suggests that partial reverse cell polarity may lead to poor prognosis of breast cancer. Overexpression of Rac1 may lead to polarity change in IDC-NOS of the breast. Therefore, Rac1 could be a therapeutic target for breast cancer.

https://journals.sagepub.com/doi/pdf/10.1177/1010428317710908

High expression of Rac1 is correlated with partial reversed cell polarity and poor prognosis in invasive ductal carcinoma of the breast

Endometrial stromal sarcoma (ESS) is a rare malignant neoplasm of the uterus. We report the first case of undifferentiated ESS (UES) coexistent with grade 1 endometrioid adenocarcinoma in a 73-year-old female who presented with irregular vaginal bleeding for 4 days after menopause 20 years. Imaging examination including Magnetic Resonance Imaging (MRI) demonstrated multi-node reflection in uterine cavity without metastatic lesions, and the endometrium essentially normal. Grossly, a grey-red breakable polypoid tumor of 4.5 × 3.0 ×2.0 cm was recognized in the posterior uterine wall with surrounding slight rough endometrium. Microscopically, the tumor was composed of a larger component of undifferentiated stromal sarcoma that was distinct from a smaller endometrioid adenocarcinoma. The separate components of the tumor could be supported in immunohistochemical studies. There was no sign of recurrence for postoperative 6 months.

Endometrial stromal sarcoma with endometrioid adenocarcinoma of the uterus: a case report.

AIM: To investigate if loss of epithelial cell adhesion molecule (EpCAM) is associated with microinvasion in hepatocellular carcinomas (HCCs) in the presence of chronic hepatitis B.

METHODS: The expression of EpCAM, cytokeratin 7 (CK7) and CK19 in 112 hepatic nodules was studied, including 20 HCCs with nodules ≤ 3 cm, 26 HCCs with nodules > 3 cm, 20 high-grade dysplastic nodules, 26 cirrhotic, large regenerative nodules and 20 cases of cirrhosis.

RESULTS: Membranes of ductular reaction (DR) hepatobiliary cells, interlobular bile duct and some hepatic cells were positive for EpCAM expression. Active expression of DR/EpCAM was observed in the majority of noninvasive nodules (50/66, 75.76%); however, expression was absent in the major area of invasion in HCCs (42/46, 91.30%). DR/EpCAM loss in HCCs ≤ 3 cm was higher than in high-grade dysplastic nodules (HGDNs) (P 3 cm, 20 HGDNs) with DR/EpCAM expression had a higher overall survival rate (P 0.05). The diagnostic specificity and diagnostic accuracy were both increased when DR/EpCAM, DR/CK7 and DR/CK19 were combined (P < 0.01).

CONCLUSION: DR/EpCAM loss may be a useful marker for determining microinvasion in HCCs ≤ 3 cm, but also for predicting prognosis.

Perinodular ductular reaction/epithelial cell adhesion molecule loss in small hepatic nodules

Objective To investigate the role of absent ductular reaction (DR) at hepatocellular-stromal boundaries in early stage hepatocellular carcinoma (HCC) with cirrhosis in patients with chronic hepatitis B. Methods Cytokeratin (CK)7 and CK19 expression was detected by the SP immunohistochemistry method in 112 hepatic nodules taken from 20 cases of early HCC, 26 cases of HCC with nodules more than 3 cm, 20 cases of high-grade dysplastic nodule (HGDN), 26 cases of low-grade dysplastic nodule (LGDN), and 20 cases of cirrhosis (CIR). DR/CK7 and DR/CK19 were assessed separately on a semi-quantitative scale and statistically analyzed. Results The mean age of the patients in the study was 53.71 years-old, and the study population consisted of 73 males and 39 females. The follow-up time ranged from 3 to 90 months. Positive CK7 and CK19 staining was detected in the cytoplasm of DR-positive hepatobiliary cells, interlobular bile duct, and a portion of hepatic cells. All of the DR/CK7- and DR/CK19-positive cells were localized around the non-invasive nodules. Specimens with focal or diffuse DR/CK7- and DR/CK19-loss had more robust stromal invasion. Specimens from early HCC cases showed greater DR/CK19 loss than specimens from HGDN cases, LGDN cases and CIR cases (all P less than 0.01). DR/CK7 loss of early HCC was less than HCC with nodules more than 3 cm (P less than 0.05), and more than LGDN cases and CIR cases (both P less than 0.01).The area under the receiver operating characteristic curve of DR/CK7 was very similar to that of DR/CK19 (P more than 0.05). Pearson's correlation analysis indicated that DR/CK7 and DR/CK19 were positively correlated with tumor-free time (P less than 0.01) and negatively correlated with early recurrence time as well as death rate (both P less than 0.01). Furthermore, cases showing DR/CK7 or DR/CK19 loss had lower overall survival rate and tumor-free survival rate (P less than 0.01) and higher early recurrence rate (P less than 0.01). Conclusion DR/CK7 and DR/CK19 immunostaining may help to distinguish non-invasive HGDNs from both minimally-invasive and overtly-invasive HCCs by identifying small foci of invasion and predicting increased risk of invasiveness.

[Diagnostic value of absent ductular reaction at hepatocellular-stromal boundaries in early stage hepatocellular carcinoma].

Epithelioid hemangioendothelioma (EHE) is a rare tumor of the urinary system. Only three cases of EHE of the bladder have been reported to date, and the biological properties of the tumor in this location remain poorly characterized. We report a case of primary EHE of the urinary bladder in a 58-year-old woman who was treated by transurethral resection and review the existing literature on the diagnosis and treatment of EHE of the bladder.

Bingbing Liu

Papers

High expression of Rac1 is correlated with partial reversed cell polarity and poor prognosis in invasive ductal carcinoma of the breast

Endometrial stromal sarcoma with endometrioid adenocarcinoma of the uterus: a case report.

Perinodular ductular reaction/epithelial cell adhesion molecule loss in small hepatic nodules

[Diagnostic value of absent ductular reaction at hepatocellular-stromal boundaries in early stage hepatocellular carcinoma].

Primary epithelioid hemangioendothelioma of the bladder: case report and review of the literature.