Molecular Mechanism and Morphology in Cancer

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the human gastrointestinal tract. GISTs are positive for the c-kit gene product, KIT, which is a receptor tyrosine kinase and are considered to derive from interstitial cells of Cajal (ICCs) which are only KIT-positive proper cells of normal gastrointestinal tract. Most GISTs have gain-of-function mutations of the c-kit gene which are considered to be a main cause of GIST development. Gain-of-function mutations of the platelet-derived growth factor receptor alpha (PDGFRA) gene are another cause of GISTs in minor proportion. Thus, GISTs could be defined as a distinctive tumor type that is derived from ICCs or their precursor and develops through aberrant KIT or PDGFRA signaling. Majority of GISTs are morphologically spindle, and the remaining cases show epithelioid form or mixed feature of spindle and epithelioid structures. GISTs with PDGFRA gene mutations are almost always epithelioid, and most of them demonstrate myxoid change.

Although the incidence of renal neoplasms is not particularly high, their clinical presentation is often interesting. They tend to arise in association with familial neoplastic syndromes, i.e. renal cell carcinoma with von Hippel-Lindau disease. The cloning of the genes responsible for these hereditary pathological conditions revealed their involvement in sporadic renal cancers. Based on their molecular biological features, the classification of renal neoplasms was reassessed by the World Health Organization in 2004. In this chapter we discuss the relationships between the pathology and molecular biology of each histological type of renal neoplasm and the underlying molecular biological abnormalities.

The current practice of relying solely on microscopic examinations for histological classification of gliomas and, consequentially, determination of optimal treatment, appears to be insufficient. As a result of the increasing use of molecular markers in tumor classification, there is an emerging emphasis in the genetic profiles of distinct subtypes of glioma. Glioblastomas classified as WHO grade IV are the most malignant astrocytic tumors and may develop either as de novo primary glioblastomas or as secondary glioblastomas arising from lower-grade astrocytomas. Both primary and secondary glioblastomas show similar histological features, but these subtypes constitute molecularly distinct entities evolving through different genetic pathways and likely to differ in prognosis and in response to therapy. The standard of care involves postoperative radiotherapy with concomitant and sequential administration of temozolomide (TMZ); however, the methylation status of O6-methylguanine-methyltransferase (O6-MGMT) appears to relate to TMZ resistance. Oligodendroglioma (WHO grade II) and anaplastic oligodendroglioma (WHO grade III) are particular glioma subtypes, derived from oligodendrocytes, that show remarkable response to a specific chemotherapy regimen of procarbazine + CCNU + vincristine (PCV), making their correct diagnosis important. Without the availability of typical morphological features, however, histological differentiation of oligodendrogliomas from astrocytoma is highly subjective. Inclusion of such molecular markers – for example, loss of heterozygosity (LOH) on chromosomes 1p and 19q, which is correlated with sensitivity to PCV chemotherapy and with increased survival in patients specifically with oligodendroglial tumors - will help to tailor treatment to the individual patient. This article reviews biological and molecular approaches to glioma classification that have the potential to increase the efficacy of treatments for these tumors.

Breast cancer has become the top killer of death worldwide among women with the number about 519,000 deaths each year, and the deaths from cancer is projected to continue rising which was reported by World Health Organization (WHO) recently. As breast cancer is a heterogenous disease whose behavior is determined by the molecular characteristics, increased interests are to unravel the molecular mechanisms of breast cancer development and progression. Bcl-2, as a protooncogene identified in 1984, contributes to malignancy by protecting cells from apoptosis. Since the identification of Bcl-2, a number of studies have been exploited to investigate their contribution to the formation, progression, therapy resistance and prognostic potential in many cancers including breast cancer. Preclinical studies have suggested that Bcl-2 overexpression enhances metastatic potential of breast cancer cells. And in general, the expression of Bcl-2 has been associated with the presence of good prognostic markers, such as hormonal receptor positivity, lower or absent p53 expression and a favorable clinical outcome. The overexpression of Bcl-2 is also associated with drug resistance or sensitivity to specific chemotherapy, radiotherapy and hormonal therapy. In recent years a number of studies have shed light onto the role of Bcl-2 in mediating the effects of anticancer agents in order to develop more efficient and more precisely targeted treatment strategy. The independent prognostic value of Bcl-2 in breast cancer is demonstrated in many recent investigations as well. The aim of this review is to give a summary of the role of Bcl-2 in breast cancer.

Chromosomal rearrangements were previously thought to be primarily the oncogenic mechanism of hematologic malignancies and sarcomas. Recently, recurrent gene fusions have been identified in the majority of prostate cancers involving E26 transformation-specific (ETS) family members of transcription factors. The most common fusion, TMPRSS2-ERG, is present in approximately 50% of prostate-specific antigen (PSA)-screened localized prostate cancer and in 15-30% of population-based cohorts. The prostate cancer gene fusions that have been identified thus far are characterized by 5' genomic regulatory elements, most commonly controlled by androgen, fused to members of the ETS family of transcription factors, leading to the overexpression of oncogenic transcription factors. To date, a growing body of evidence suggests that ETS gene fusions may define a distinct molecular class of prostate cancer. In this review, I summarize the discovery, characterization and detection of the ETS gene fusions, current understanding of their roles in prostate cancer biology, association with prognosis as well as morphological aspect from the point of view of pathology.

Recently a unique cell death caused by microwaves was reported as a new type of cell death by our group. This paper explains about cell death caused by microwaves and its similarity to radiofrequency ablation (RFA), in clinical use for cancer therapy, and compares it with other forms of cell death (oncosis, apoptosis, programmed cell death, caspase-independent cell death, and autophagy). Microwave cell death (MCD) and radiofrequency ablation cell death (RFACD) are characterized by a well-preserved morphology and antigenicity for a long period under light microscopic examination, which differ from other known forms of cell death. We have pointed out the loss of enzyme activity and abnormal DNA electrophoresis in MCD. Until this discovery, it was difficult for pathologists to evaluate whether carcinoma was viable or not after microwave coagulation therapy (MCT) or RFA therapy, when a tissue biopsy specimen was processed under routine tissue preparation for histological or cytological diagnosis, such as formalin fixation, paraffin embedding, and hematoxylin-eosin staining or ethanol fixation and Papanicolaou staining, respectively. New criteria using enzyme histochemistry or other molecular methods are essential to evaluate the therapeutic effects in MCD or RFACD.

Thyroid carcinoma is the most prevalent type of endocrine cancer and its incidence has reportedly increased significantly over the last few decades in many areas of the world. The traditional classification of thyroid carcinoma divides it into four common types, including papillary, follicular, medullary and anaplastic carcinomas. In recent years, much progress has been made regarding the molecular characterization of these carcinomas, clarifying the genetic alterations underlying the histotype diversity of these types of cancer. The most common mutations in thyroid cancer are point mutations of the BRAF, RAS, p53 and β-catenin genes, and RET/PTC and PAX8-PPARγ rearrangements. Many of these mutations, particularly those leading to activation of the MAPK pathway, are being actively explored as therapeutic targets for thyroid cancer. In this review we have summarized these specific genetic changes in the process of development and dedifferentiation in thyroid cancer derived from thyroid follicular cells.

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