The genes of cellular cooperation that evolved with multicellularity about a billion years ago are the same genes that malfunction to cause cancer. We hypothesize that cancer is an atavistic condition that occurs when genetic or epigenetic malfunction unlocks an ancient 'toolkit' of pre-existing adaptations, re-establishing the dominance of an earlier layer of genes that controlled loose-knit colonies of only partially differentiated cells, similar to tumors. The existence of such a toolkit implies that the progress of the neoplasm in the host organism differs distinctively from normal Darwinian evolution. Comparative genomics and the phylogeny of basal metazoans, opisthokonta and basal multicellular eukaryotes should help identify the relevant genes and yield the order in which they evolved. This order will be a rough guide to the reverse order in which cancer develops, as mutations disrupt the genes of cellular cooperation. Our proposal is consistent with current understanding of cancer and explains the paradoxical rapidity with which cancer acquires a suite of mutually-supportive complex abilities. Finally we make several predictions and suggest ways to test this model.

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Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors.

The reported incidence of neoplasia in the extinct human lineage is rare, with only a few confirmed cases of Middle or Later Pleistocene dates reported. It has generally been assumed that pre-modern incidence of neoplastic disease of any kind is rare and limited to benign conditions, but new fossil evidence suggests otherwise. We here present the earliest identifiable case of malignant neoplastic disease from an early human ancestor dated to 1.8–1.6 million years old. The diagnosis has been made possible only by advances in 3D imaging methods as diagnostic aids. We present a case report based on re-analysis of a hominin metatarsal specimen (SK 7923) from the cave site of Swartkrans in the Cradle of Humankind, South Africa. The expression of malignant osteosarcoma in the Swartkrans specimen indicates that whilst the upsurge in malignancy incidence is correlated with modern lifestyles, there is no reason to suspect that primary bone tumours would have been any less frequent in ancient specimens. Such tumours are not related to lifestyle and often occur in younger individuals. As such, malignancy has a considerable antiquity in the fossil record, as evidenced by this specimen.

/pdf/earliest-hominin-cancer-1-7-million-year-old-osteosarcoma-2y57jntzs7.pdf

Earliest hominin cancer: 1.7-million-year- old osteosarcoma from Swartkrans Cave, South Africa

SUMMARY

We compared the maturation pathway of normal and psoriatic epidermis using three different markers: (I) Involucrin, which is normally detected in the stratum granulosum in normal skin, was detected in all but the basal layer of involved psoriatic skin; (2) an antigen, recognized by the murine monoclonal antibody Ψ3, was present in all but the basal layer of involved psoriatic skin but was absent from uninvolved and normal skin; (3) fibronectin, which normally localizes in the dermis and the epidermal-dermal junction, was also detected intra- and extracellularly in the psoriatic epidermis. These results indicate that the alterations in keratinocyte maturation found in psoriasis do not arise from a truncation of the normal maturation pathway but rather reflect the onset of an abnormal pathway of differentiation characterized by the expression of Ψ3 antigen and fibronectin and the premature appearance of involucrin.

Abnormal maturation pathway of keratinocytes in psoriatic skin.

Metastasis-associated gene or metastasis tumor antigen 1 (MTA1) is a new member of cancer progression-related gene family. It was first identified in rat mammary adenocarcinoma and later recognized as an important constituent of nucleosomal remodeling complex (NuRD), displaying dual regulatory functions as a co-repressor and co-activator for a large number of genes. Chromatin remodelers are ATP-dependent multi-protein chromatin modifying machines. These complexes alter the nucleosome positioning regulating the accessibility of genomic DNA to various transcription factors and thus modulate eukaryotic gene transcription. Since its identification two decades ago, MTA1 has been reported to be overexpressed in many cancers. Moreover, its overexpression has also been correlated with transformation and tumor progression. Furthermore, MTA1 has been shown to modulate the response of several tumor suppressor genes like p53 and oncogenes like c-myc. Taken together, current literature suggests that MTA proteins, especially MTA1, act as a master co-regulatory molecule involved in the carcinogenesis and progression of various malignant tumors. The primary focus of this review is to provide an overview of the MTA proteins with special emphasis on its role in cancer and use as a marker for cancer progression and potential target for therapy.

Clinical implications of MTA proteins in human cancer.

Metaphysical presuppositions are important for guiding scientific practices and research. The success of twentieth‐century biology, for instance, is largely attributable to presupposing that complex biological processes are reducible to elementary components. However, some biologists have challenged the sufficiency of reductionism for investigating complex biological phenomena and have proposed alternative presuppositions like organicism. In this article, contemporary cancer research is used as a case study to explore the importance of metaphysical presuppositions for guiding research. The predominant paradigm directing cancer research is the somatic mutation theory, in which mutated genes are presumed to be ultimately responsible for explaining carcinogenesis. This reductionistic approach to cancer has been criticised recently, and an organistic approach has been proposed. The article concludes with a discussion of the reciprocal interaction of metaphysical presuppositions and scientific practices for in...

Metaphysical presuppositions and scientific practices: Reductionism and organicism in cancer research

Gene transfer experiments have made it possible to detect active transforming sequences in the DNA of various human tumor cells. These sequences, the cellular oncogenes, have been found in tumors as diverse as neuroblastomas, leukemias, carcinomas, and sarcomas . They appear to represent molecular determinants that participate in transformation mechanisms that are common to a wide variety of tumors . From this perspective, cancer seems to be a single, unitary disease, and not 100 different diseases, each characterized by a different type of tumor. Several ofthese oncogenes have been isolated by molecular cloning (1-4) . The most well studied of these is one from a human bladder carcinoma cell line, referred to as T24/EJ . Use of this oncogene in sequence hybridization has revealed a property common to this and the other cellular oncogenes : these oncogenes derive from closely related antecedent genes residing in the normal cellular genome . It appears that these normal genes, often called \"proto-oncogenes,\" become converted into oncogenes via processes of \"somatic mutation.\" This last conclusion remains equivocal, if only because there is little direct evidence to date showing comparison of the oncogene of a tumor with the homologous sequences of closely lying normal tissue . A variety of mechanisms might be imagined to be responsible for the conversion of a proto-oncogene into an active oncogene. In the case of the bladder carcinoma oncogene, a remarkably simple mechanism was revealed within the last year . Comparison ofthe bladder carcinoma oncogene with its normal antecedent showed that a single nucleotide alteration, occurring in the protein-encoding portion of the gene, was responsible for the activation . This point mutation affected the twelfth amino acid of the encoded 21,000-dalton protein causing the replacement of a glycine by a valine (5-9). Since little is known about the functioning of this protein, it is impossible at present to explain how such a subtle alteration can have such profound effects on this protein, and in turn, on cellular physiology . This bladder carcinoma proto-oncogene has homologs in the DNA of all vertebrates . Its evolutionary origins can, however, be traced back much further. Sequence hybridization has found homologs of this and other proto-oncogenes PERSPECTIVES

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Weinberg Ra

Papers

Oncogenes and the molecular biology of cancer.