The Cancer Cell and the Tumor Stroma: Pathological and Biological Foundations (copy) (copy)

Overview of Cancer and the Tumor Stroma

• Definition of Cancer: Cancer is defined as a malignant tumor or cancer disease. It is primarily characterized as a disease of the cell caused by the deregulation of the cellular genetic program, fundamentally representing a pathology of the DNA.

• Consequences of Genetic Deregulation:     * Uncontrolled proliferation of abnormal cells.     * Local and/or distant invasion (metastasis).     * Potential for recurrence after treatment, leading to a poor prognosis.

• Composition of Cancer Tissue: Cancer tissue is composed of two distinct but interacting components:     1. The Cancer Cell.     2. The Stroma (Tumor Stroma).

Objectives of the Study of Cancer Cells and Stroma

• To understand the specific characteristics of the cancer cell that are responsible for its proliferation and aggressiveness.

• To define the tumor stroma, specifying its biological origin and its main structural and cellular components.

• To understand the diagnostic and prognostic value of the tumor stroma in clinical practice.

The Cancer Cell: Biological Foundation

• Core Transformation: A cancer cell loses specific normal characteristics and acquires abnormal morphological and/or functional features.

• Key Results of Transformation:     * Autonomy: The cell operates independently of normal regulatory systems.     * Uncontrolled Growth: Proliferation occurs without standard biological constraints.

• Rationale for Studying Cancer Cell Characteristics:     * Cancer Screening: Identifying early signs of cellular change.     * Diagnosis of Malignancy: Note that no single feature alone is sufficient to confirm malignancy; it requires a combination of findings.     * Refining Prognosis: Determining the likely course of the disease.     * Guiding Treatment: Tailoring therapy based on cellular traits.

• Study Materials: Diagnostic material is obtained via:     * Cytological Samples: Examination of isolated cells or cell clusters.     * Tissue Samples: Histological examination of preserved tissue architecture.

Main Characteristics of Cancer Cells

Cancer cells display six primary types of alterations:

1. Morphological Changes.

2. Cell Membrane Alterations.

3. Behavioral Changes.

4. Alterations in Intercellular Regulatory Signals.

5. Functional Properties.

6. Genetic Abnormalities.

1. Morphological Changes

• Diagnostic Significance: These changes are the major criteria for cancer diagnosis.

• Comparison of Study Methods:     * Cytology: Involves isolated cells or clusters smeared on a slide. It allows for the optimal analysis of cytonuclear details. Metaphor: "Opening the door, displacing the cells from their home, and putting them under a microscope."     * Histology: Mandatory for a definitive diagnosis. It studies both the tumor cells and the stroma together, allowing for the evaluation of architectural abnormalities that cannot be seen in cytology. Metaphor: "Picking up the house (tissue) and putting it under a microscope to see the house with the cells in it."     * Diagnosis Constraint: A cytological diagnosis is only suggestive; it must be confirmed by histological examination (e.g., a cervical biopsy following a suggestive Pap smear) before initiating treatment.

Nuclear Changes (7 Main Criteria)

Nuclear abnormalities are due to quantitative and structural chromatin defects:

1. Anisocytosis: Variation in cell size.

2. Anisocaryosis: Variation in the size of the nuclei.

3. Hyperchromasia: Darkly stained nuclei due to increased DNA content.

4. Increased Nuclear-to-Cytoplasmic (N/C) Ratio.

5. Prominent Nucleolus: Enlarged or multiple nucleoli.

6. Increased Mitotic Index: Frequent cellular division.

7. Abnormal Mitoses: The presence of atypical mitotic figures such as tripolar or tetrapolar divisions, as opposed to normal bipolar mitosis.

Limitations of Morphological Diagnosis

• Mimicry: Non-cancerous cells may show similar changes due to inflammation, viral infection, radiotherapy, or chemotherapy.

• Behavior vs. Appearance: A cancer cell may look morphologically normal but behave aggressively (e.g., forming tumor emboli or metastases).

• Distribution: Not all criteria are present in every single cell; they must be sought across various cells in a sample.

• Diagnostic Synthesis: Since no single morphological feature is specific to malignancy, the diagnosis relies on a combination of arguments.

2. Cell Membrane Alterations

• Antigenic Changes: Loss of normal membrane antigens and the acquisition of new tumor antigens that are absent in normal cells.

• Recognition: Results in abnormal cell recognition.

• Adhesion: Loss of intercellular adhesion, facilitating cell detachment.

• Signaling: Abnormal transmission of regulatory signals affecting cellular division, movement, and metabolism.

3. Behavioral Changes

In Vivo (Inside the Body)

• Autonomy: Escape from homeostasis and hormonal dependence.

• Immortality: Indefinite proliferation that continues until the death of the host.

• Disorganized Proliferation: Lack of structured growth.

• Metastatic Potential: The ability to spread to distant sites.

In Vitro (Laboratory Culture)

• Loss of Intercellular Adhesion.

• Loss of Contact Inhibition: Normal cells stop dividing when they touch; cancer cells continue to proliferate and overlap, demonstrating invasive potential.

• Aggressiveness: Hostility toward normal cells.

• Infinite Proliferation: Continued growth in culture as long as adequate nutrients are provided.

4. Alterations in Intercellular Regulatory Signals

• Signal Transmission: There is a loss of the ability to regulate growth through signals between cells.

• Growth Factors: Acquisition of new growth factors specific to cancer cells, which stimulate mitotic activity and enhance tumor growth.

5. Functional Properties

Functional changes in cancer cells can be categorized in three ways:

1. Preservation of Normal Functions: These cells resemble the tissue of origin. They are morphologically recognizable and are termed well-differentiated tumors.     * Examples: Mucin secretion in adenocarcinoma; keratin production in squamous cell carcinoma.

2. Loss of Normal Functions: The cells show no resemblance to the tissue of origin. Their morphology is unrecognizable, and they are termed undifferentiated tumors.     * Examples: An adenocarcinoma that does not produce mucin; a squamous cell carcinoma that does not produce keratin.

3. Acquisition of New Functions: Abnormal synthesis of tumor markers. These are substances synthesized by the cancer cells themselves.     * Detection: Via blood, urine, or indirectly through immunohistochemistry (IHC).     * Utility: Useful for diagnosis and monitoring the response to treatment.

6. Genetic Abnormalities

Chromosomal Abnormalities

• Qualitative Changes:     * Deletion: Loss of a whole chromosome or a fragment.     * Translocation: Transfer of a fragment from one chromosome to another.

• Quantitative Changes:     * The number of chromosomes varies considerably compared to normal cells.     * Aneuploidy: Abnormal number of chromosomes.     * Polyploidy: Possession of more than two complete sets of chromosomes.امتلاك أكثر من مجموعتين كاملتين من الكروموسومات

II- Tumor Stroma

• Definition: The tumor stroma (or reaction stroma) is the connective-vascular component present in cancer. It is the supportive tissue surrounding the tumor cells.

• Nature: It is a non-tumor tissue originating from the host (non-neoplastic). Stromal cells do not carry the genetic abnormalities found in tumor cells.

• Function:     * Provides structural support and nutrition.     * Allows the tumor to grow beyond a minimal volume.     * Plays a critical role in metastatic dissemination.     * Acts as a necessary condition for tumor development and growth.

• Evolution: It comprises both pre-existing host elements and newly formed elements.

Stroma Formation (Genesis)

Stroma formation involves two main processes:

A) Neoangiogenesis (Neovascularization)

• Process: The proliferation of new blood vessels under the influence of angiogenic factors. It involves the degradation of the basement membrane, followed by the proliferation, migration, and sprouting of endothelial cells from pre-existing capillaries.

• The Tumor's Circulatory System:     * Connected to normal arteriovenous pedicles.     * Exclusively of the capillary type.

• Angiogenic Balance:     * Activators (ON): $VEGF$, $bFGF$, $PIGF$, Angiopoietins, $PDGF$.     * Inhibitors (OFF): Thrombospondin, Angiostatin, Endostatin, Vasoinhibin, Tumstatin.

• Vessel Characteristics:     * The walls of new vessels are very fragile and prone to rupture, leading to intratumoral hemorrhages.     * If neovascularization is insufficient, it leads to marked tumor necrosis due to lack of nutrients and oxygen.

B) Inflammatory Reaction and Fibroblastic Proliferation

• Host Response: This reaction occurs locally at the site of tumor growth.

• Immune Influx: An influx of lymphocytes (cytotoxic T-lymphocytes, antibody-secreting B-lymphocytes), cytotoxic macrophages, and histiocytes appearing at the tumor periphery.

• Fibroblast Activation: Following the immune response, activated fibroblasts build the connective tissue structure.

Composition and Types of Stroma

Composition

• Connective Tissue Components:     * Fibroblasts and myofibroblasts.     * Inflammatory cells (Lymphocytes, Mast cells, Macrophages).     * Fibers and ground substance.     * Residual and newly formed vessels (Endothelial cells, Pericytes).     * Extracellular matrix, proteases, and protease inhibitors.

• Tumor Type Variation:     * Carcinomas: Stroma is especially well-developed.     * Sarcomas: Stroma is reduced to a vascular network feeding often lacunar pseudo-vessels.

Types of Stroma and Prognostic Value

1. By Abundance of Connective Tissue Fibers:     * Abundant Stromal Reaction: Often associated with a better prognosis as it may reflect slow tumor progression.     * Sparse Stromal Reaction: Often associated with a poor prognosis.

2. By Type of Vascularization:     * Few Capillaries: Causes tumor necrosis due to anoxia.     * Many Capillaries: Leads to intratumoral hemorrhages.     * Organoid Vascular Architecture: Characteristically seen in endocrine tumors.     * Endothelial Proliferation: Seen in glioblastomas.

3. Inflammatory Stroma:     * The quality of inflammation can have a favorable prognostic value (e.g., in breast or gastric cancers).     * Lymphocytic: Found in medullary carcinoma of the breast.     * Plasmacytic: Found in Kaposi’s sarcoma.     * Neutrophilic/Eosinophilic: Suggests secondary infection of surface cancers (skin, aerodigestive tract).     * Epithelioid and Giant Cell Granulomatous: Seen in testicular seminoma.     * Utility: Can help detect microinvasion foci (e.g., lymphoid reaction in cervical cancer).

4. By State of the Ground Substance:     * Hyaline Transformation: Dense, glassy collagen seen in adenoid cystic carcinoids.     * Amyloid Deposits: Seen in medullary thyroid carcinoma.     * Calcifications (Psammoma Bodies): Found in papillary carcinoma of the thyroid and ovary.

Key Messages

• Cancer tissue consists of the cancer cell plus the stroma.

• Histological diagnosis relies on a combination of features; no single morphological criterion is sufficient for malignancy.

• The tumor stroma is non-neoplastic, host-induced, and essential for tumor development, growth, and metastasis ($++$).