Circulating tumor cell-derived organoids: Current challenges and promises in medical research and precision medicine

Publication date: Available online 31 January 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Prakash P. Praharaj, Sujit K. Bhutia, Sunitha Nagrath, Rhonda L. Bitting, Gagan Deep
Traditional 2D cell cultures do not accurately recapitulate tumor heterogeneity, and insufficient human cell lines are available. Patient-derived xenograft (PDX) models more closely mimic clinical tumor heterogeneity, but are not useful for high-throughput drug screening. Recently, patient-derived organoid cultures have emerged as a novel technique to fill this critical need. Organoids maintain tumor tissue heterogeneity and drug-resistance responses, and thus are useful for high-throughput drug screening. Among various biological tissues used to produce organoid cultures, circulating tumor cells (CTCs) are promising, due to relative ease of ascertainment. CTC-derived organoids could help to acquire relevant genetic and epigenetic information about tumors in real time, and screen and test promising drugs. This could reduce the need for tissue biopsies, which are painful and may be difficult depending on the tumor location. In this review, we have focused on advances in CTC isolation and organoid culture methods, and their potential applications in disease modeling and precision medicine.



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Fusion genes: A promising tool combating against cancer

Publication date: Available online 31 January 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Xiaofeng Dai, Rutaganda Theobard, Hongye Cheng, Mengtao Xing, Jianying Zhang
The driving roles of fusion genes during tumorigenesis have been recognized for decades, with efficacies demonstrated in clinical diagnosis and targeted therapy. With advances in sequencing technologies and computational biology, a surge in the identification of fusion genes has been witnessed during the past decade. The discovery and presence of splicing based fusions in normal tissues have challenged our canonical conceptions on fusion genes and offered us novel medical opportunities. The specificity of fusion genes to neoplastic tissues and their diverse functionalities during carcinogenesis foster them as promising tools in the battle against cancer. It is time to re-visit and comb through our cutting-edge knowledge on fusion genes to accelerate clinical translation of these internal markers. Urged as such, we are encouraged to categorize fusion events according to mechanisms leading to their generation, oncological consequences and clinical implications, offer insights on fusion occurrence across tumors from the system level, highlight feasible practices in fusion-related pharmaceutical development, and identify understudied yet important niches that may lead future research trend in this field.



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Colorectal cancer prevention: Immune modulation taking the stage

Publication date: Available online 31 January 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Rochelle Fletcher, Yi-Jun Wang, Robert E. Schoen, Olivera J. Finn, Jian Yu, Lin Zhang
Prevention or early detection is one of the most promising strategies against colorectal cancer (CRC), the second leading cause of cancer death in the US. Recent studies indicate that antitumor immunity plays a key role in CRC prevention. Accumulating evidence suggests that immunosurveillance represents a critical barrier that emerging tumor cells have to overcome in order to sustain the course of tumor development. Virtually all of the agents with cancer preventive activity have been shown to have an immune modulating effect. A number of immunoprevention studies aimed at triggering antitumor immune response against early lesions have been performed, some of which have shown promising results. Furthermore, the recent success of immune checkpoint blockade therapy reinforces the notion that cancers including CRC can be effectively intervened via immune modulation including immune normalization, and has stimulated various immune-based combination prevention studies. This review summarizes recent advances to help better harness the immune system in CRC prevention.



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Reformation in chimeric antigen receptor based cancer immunotherapy: Redirecting natural killer cell

Publication date: Available online 31 January 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Chu Lin, Jun Zhang
Natural killer (NK) cells are an important subset of lymphocytes which play a critical role in host immunity against cancer. With MHC-independent recognition, short lifespan and potent cytotoxicity, NK cells make a promising candidate for chimeric antigen receptor (CAR)-engineered cancer immunotherapy. Due to innate biological properties of NK cells, CAR-NK may outperform CAR-T therapy in terms of less side effects and more universal access, which may become a great reformation in CAR-based cancer immunotherapy. The CARs used in peripheral blood (PB) NK cells as well as NK cell line like NK-92 are the most important outfits defining antigenic specificity. The constructs of CARs used in NK cells from different sources vary, which all undergo generational optimization. The anti-tumor effect of CAR-NK has been validated in numerous preclinical trials for cancers, including hematological malignancies and many solid tumors, which provides evidence for potential clinical application of CAR-NK. Additionally, this review concludes the challenges faced in the application of CAR-NK. Although CAR-NK is considered as one of the most possible "off-the shelf" product, the improvement for the efficiency of expansion and transduction and the solution for underlying safety issue are still needed. Possible coping strategies for challenges and upgrades in techniques are also highlighted for future development in CAR-NK cancer immunotherapy.



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Obesity linking to hepatocellular carcinoma: A global view

Publication date: Available online 31 January 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Lu Gan, Zhenjiang Liu, Chao Sun
Hepatocellular carcinoma (HCC) is the commonest primary liver cancer and the second leading cause of cancer death worldwide. Obesity is rapidly becoming pandemic and associated with increased carcinogenesis. In this review, we describe the obesity-related factors that influence the development of HCC. We provide evidence of strong links between neural regulation, endocrine and HCC in obesity. We discuss recent advances in our understanding of how adipose tissue alters hepatic metabolism and immune response in HCC development through inter-organ communication. Taken together, our review aims to provides a concise and up-to date summary about the connection between obesity and HCC, with emphasis on the opportunities for effective strategies in preventing the development of HCC in obese individuals.



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Chaperoning the Guardian of the genome the two-faced role of molecular chaperones in tumor suppressor p53 action

Publication date: Available online 31 January 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Bartosz Wawrzynow, Alicja Zylicz, Maciej Zylicz
Organized networks of heat shock proteins, which possess molecular chaperone activity, protect cells from abrupt environmental changes. Additionally, molecular chaperones are essential during stress-free periods, where they moderate housekeeping functions. During tumorigenesis these chaperone networks are extensively remodeled in such a way that they are advantageous to the transforming cell. Molecular chaperones by buffering critical elements of signaling pathways empower tumor evolution leading to chemoresistance of cancer cells. Controversially, the same molecular chaperones, which are indispensable for p53 in reaching its tumor suppressor potential, are beneficial in adopting an oncogenic gain of function phenotype when TP53 is mutated. On the molecular level, heat shock proteins by unwinding the mutant p53 protein expose aggregation-prone sites leading to the sequestration of other tumor suppressor proteins causing inhibition of apoptosis and chemoresistance. Therefore, within this review therapeutic approaches combining classical immuno- and/or chemotherapy with specific inhibition of selected molecular chaperones shall be discussed.



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Reinterpreting Polarity and Cancer: The changing landscape from tumor suppression to tumor promotion

Publication date: Available online 31 January 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Yasuhiro Saito, Ridhdhi R. Desai, Senthil K. Muthuswamy
Cell polarity is a fundamental property used to generate asymmetry and structure in all cells. Cancer is associated with loss of cell and tissue structure. While observations made in model system such as Drosophila, identify polarity regulators as tumor suppressors that cause inappropriate cell division, studies in mammalian epithelia do not always support such a causative contribution. Our analysis of published cancer dataset shows that many polarity genes, including PARD6B, SCRIB, PRKCI, DLG1, DLG2, DLG5 and LLGL2, are frequently amplified in multiple cancers raising the possibility that mammalian epithelia may have evolved to use polarity proteins in multiple ways where they may have tumor promoting functions. In this review, we reinterpret the published results and propose a modified perspective for the role of polarity regulators in cancer biology. In addition to the traditional form of cell polarity, which is involved establishment of maintenance of normal cell structure and asymmetry, we propose that some mammalian polarity proteins also regulate subcellular polarity (intracellular asymmetry), which can improve cellular fitness to carry out functions such as proliferation, apoptosis, stress adaptation, stemness and organelle biology. Here, we define subcellular polarity and discuss evidence that supports a role for subcellular polarity in biology.



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